Save up to 80% by drug discount in your pharmacy with "Pharmacy Near Me - National Drug Discount Card"
You can scan QR Code(just open camera on your phone/scan by application) from the image on prescription drug discount card to save it to your mobile phone. Or just click on image if you're on mobile phone.
| Product NDC Code | 66215-814 | ||||||
|---|---|---|---|---|---|---|---|
| Drug Name | Opsynvi |
||||||
| Type | Brand | ||||||
| Pharm Class | Endothelin Receptor Antagonist [EPC], Endothelin Receptor Antagonists [MoA], Phosphodiesterase 5 Inhibitor [EPC], Phosphodiesterase 5 Inhibitors [MoA] |
||||||
| Active Ingredients |
|
||||||
| Route | ORAL | ||||||
| Dosage Form | TABLET, FILM COATED | ||||||
| RxCUI drug identifier | 2677765, 2677771, 2677773, 2677775 |
||||||
| Application Number | NDA218490 | ||||||
| Labeler Name | Actelion Pharmaceuticals US, Inc. | ||||||
| Packages |
|
||||||
| Check if available Online | Get Medication Prices online with Discount |
Overdosage of OPSYNVI
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because macitentan is highly protein-bound. Macitentan Macitentan has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed. Tadalafil Single doses of tadalafil up to 500 mg have been given to healthy male subjects, and multiple daily doses up to 100 mg have been given to male patients with erectile dysfunction. Adverse reactions were similar to those seen at lower doses. Doses greater than 40 mg have not been studied in patients with PAH. Hemodialysis contributes negligibly to tadalafil elimination.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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 (5.3) ] Hypotension [see Warnings and Precautions (5.4) ] Decrease in Hemoglobin [see Warnings and Precautions (5.5) ] Visual Loss [see Warnings and Precautions (5.7) and Patient Counseling Information (17) ] Hearing loss [see Warnings and Precautions (5.8) ] Fluid Retention [see Warnings and Precautions (5.9) ] Prolonged Erection [see Warnings and Precautions (5.12) ] 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.
| 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 |
OPSYNVI Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.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 ) 7.1 Nitrates Administration of nitrates within 48 hours after the last dose of OPSYNVI is contraindicated [see Contraindications (4.3) ] . 7.2 Strong 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) ]. 7.3 Strong 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) ]. 7.4 Moderate 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) ]. 7.5 Alpha-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 (5.4) and Clinical Pharmacology (12.2) ]. 7.6 Antihypertensives 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) ]. 7.7 Alcohol 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) ].
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Macitentan Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro . The clinical impact of dual endothelin blockage is unknown. Tadalafil Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). PAH is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum, vascular smooth muscle, visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4 and PDE7, enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also > 9,000-fold more potent for PDE5 than for PDE8, PDE9 and PDE10. 12.2 Pharmacodynamics Pharmacodynamic studies with OPSYNVI have not been conducted. As OPSYNVI contains macitentan and tadalafil, the pharmacodynamic effects for each component should be considered. Pulmonary Hemodynamics of Macitentan The SERAPHIN clinical efficacy study in patients with PAH assessed hemodynamic parameters in a subset of patients after 6 months of treatment. Patients treated with macitentan 10 mg (N=57) achieved a median reduction of 37% (95% CI 22–49) in pulmonary vascular resistance and an increase of 0.6 L/min/m 2 (95% CI 0.3–0.9) in cardiac index compared to placebo (N=67). Effects on Cardiac Electrophysiology Macitentan In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval. Tadalafil In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, a single dose of 100 mg tadalafil (2.5 times the recommended dosage) had no significant effect on the QTc interval. Effects on Blood Pressure When Administered with Nitrates In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use OPSYNVI in patients taking any form of nitrates [see Contraindications (4.3) ]. A double–blind, placebo–controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for 7 days and then were given a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre–specified timepoints following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). A significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure-lowering effects at this timepoint. After 48 hours, the interaction was not detectable [see Contraindications (4.3) ]. Effects on Vision Single oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth–Munsell 100–hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (<0.1% of patients). Dose-Response Relationship Dose-response relationships, between 20 mg and 40 mg of tadalafil, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynes*sec*cm and -209 dynes*sec*cm at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively. 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
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Macitentan Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro . The clinical impact of dual endothelin blockage is unknown. Tadalafil Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). PAH is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum, vascular smooth muscle, visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4 and PDE7, enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also > 9,000-fold more potent for PDE5 than for PDE8, PDE9 and PDE10.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Pharmacodynamic studies with OPSYNVI have not been conducted. As OPSYNVI contains macitentan and tadalafil, the pharmacodynamic effects for each component should be considered. Pulmonary Hemodynamics of Macitentan The SERAPHIN clinical efficacy study in patients with PAH assessed hemodynamic parameters in a subset of patients after 6 months of treatment. Patients treated with macitentan 10 mg (N=57) achieved a median reduction of 37% (95% CI 22–49) in pulmonary vascular resistance and an increase of 0.6 L/min/m 2 (95% CI 0.3–0.9) in cardiac index compared to placebo (N=67). Effects on Cardiac Electrophysiology Macitentan In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval. Tadalafil In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, a single dose of 100 mg tadalafil (2.5 times the recommended dosage) had no significant effect on the QTc interval. Effects on Blood Pressure When Administered with Nitrates In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use OPSYNVI in patients taking any form of nitrates [see Contraindications (4.3) ]. A double–blind, placebo–controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for 7 days and then were given a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre–specified timepoints following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). A significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure-lowering effects at this timepoint. After 48 hours, the interaction was not detectable [see Contraindications (4.3) ]. Effects on Vision Single oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth–Munsell 100–hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (<0.1% of patients). Dose-Response Relationship Dose-response relationships, between 20 mg and 40 mg of tadalafil, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynes*sec*cm and -209 dynes*sec*cm at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.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
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 ) Concomitant Organic Nitrates ( 4.3 ) Concomitant Guanylate Cyclase (GC) Stimulators ( 4.4 ) 4.1 Pregnancy 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) ] . 4.2 Hypersensitivity 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 Concomitant Organic Nitrates 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.
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION OPSYNVI ® is a single tablet combination containing two oral components used to treat pulmonary arterial hypertension: macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor. Macitentan Macitentan is an endothelin receptor antagonist. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4- pyrimidinyl]-N'-propylsulfamide. It has a molecular formula of C 19 H 20 Br 2 N 6 O 4 S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula: Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive. Chemical Structure Tadalafil Tadalafil, an oral treatment for pulmonary arterial hypertension, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C 22 H 19 N 3 O 4 representing a molecular weight of 389.41. The structural formula is: The chemical designation is pyrazino[1´,2´:1,6]pyrido[3,4–b]indole-1,4-dione, 6-(1,3- benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. Chemical Structure OPSYNVI OPSYNVI is available as 10 mg/20 mg macitentan/tadalafil and 10 mg/40 mg macitentan/tadalafil film-coated tablets for oral administration. Each OPSYNVI core tablet contains the following inactive ingredients: Hydroxypropyl cellulose, hydroxypropyl cellulose (low-substituted), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, sodium starch glycolate, sodium lauryl sulfate. OPSYNVI 10 mg/20 mg tablets are film-coated with a coating material containing hydroxypropyl methylcellulose, iron oxide red, iron oxide yellow, lactose monohydrate, talc, titanium dioxide, and triacetin. OPSYNVI 10 mg/40 mg tablets are film-coated with a coating material containing hydroxypropyl methylcellulose, lactose monohydrate, talc, titanium dioxide, and triacetin.
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.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 Obtain a pregnancy test in females of reproductive potential prior to OPSYNVI treatment, monthly during treatment and one month after stopping OPSYNVI. Initiate treatment with OPSYNVI in females of reproductive potential only after a negative pregnancy test [see Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.3) ].
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS OPSYNVI is available as: 10 mg/20 mg Pink Oblong Film-coated "1020" on one side and "MT" on the other side 10 mg/40 mg White to almost-white Oblong Film-coated "1040" on one side and "MT" on the other side Film-coated tablets: Macitentan 10 mg and tadalafil 20 mg ( 3 ) Macitentan 10 mg and tadalafil 40 mg ( 3 )
| 10 mg/20 mg | Pink | Oblong | Film-coated | "1020" on one side and "MT" on the other side |
| 10 mg/40 mg | White to almost-white | Oblong | Film-coated | "1040" on one side and "MT" on the other side |
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.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) ] .
Spl product data elements
Usually a list of ingredients in a drug product.OPSYNVI macitentan and tadalafil HYDROXYPROPYL CELLULOSE, UNSPECIFIED LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYSORBATE 80 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A SODIUM LAURYL SULFATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE TRIACETIN MACITENTAN MACITENTAN TADALAFIL TADALAFIL white to almost white oblong 1040;MT OPSYNVI macitentan and tadalafil HYDROXYPROPYL CELLULOSE, UNSPECIFIED LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYSORBATE 80 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A SODIUM LAURYL SULFATE HYPROMELLOSE, UNSPECIFIED FERRIC OXIDE RED FERRIC OXIDE YELLOW TALC TITANIUM DIOXIDE TRIACETIN MACITENTAN MACITENTAN TADALAFIL TADALAFIL oblong 1020;MT
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology and/or Pharmacology Macitentan In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans. There were no adverse liver findings in long-term studies conducted in mice, rats and dogs at exposures of 12-to 116-fold the human exposure. Tadalafil Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1-to 17-fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1-and 6-month studies at unbound tadalafil exposure of 0.5-to 38-fold the human exposure (AUC) at the MRHD of 40 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4-to 10-fold the human exposure at the MRHD of 40 mg. The abnormal blood-cell findings were reversible within 2 weeks upon removal of the drug.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Macitentan Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3-and 42-fold in male and female rats, respectively. Tadalafil Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5-fold for mice, and 7-and 14-fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg. Mutagenesis Macitentan Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats. Tadalafil Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays. Impairment of Fertility Macitentan Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected. Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19-to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years. Tadalafil There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6-fold for males or 17-fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment-related non-reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20–100% of the dogs that resulted in a decrease in spermatogenesis in 40–75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no-observed-adverse-effect-level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg. There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Macitentan Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3-and 42-fold in male and female rats, respectively. Tadalafil Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5-fold for mice, and 7-and 14-fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg. Mutagenesis Macitentan Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats. Tadalafil Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays. Impairment of Fertility Macitentan Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected. Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19-to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years. Tadalafil There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6-fold for males or 17-fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment-related non-reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20–100% of the dogs that resulted in a decrease in spermatogenesis in 40–75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no-observed-adverse-effect-level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg. There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years. 13.2 Animal Toxicology and/or Pharmacology Macitentan In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans. There were no adverse liver findings in long-term studies conducted in mice, rats and dogs at exposures of 12-to 116-fold the human exposure. Tadalafil Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1-to 17-fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1-and 6-month studies at unbound tadalafil exposure of 0.5-to 38-fold the human exposure (AUC) at the MRHD of 40 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4-to 10-fold the human exposure at the MRHD of 40 mg. The abnormal blood-cell findings were reversible within 2 weeks upon removal of the drug.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 10 mg/20 mg Tablet Bottle Carton NDC 66215-812-30 Rx only Opsynvi ® (macitentan and tadalafil) tablets 10 mg / 20 mg Attention: Dispense the enclosed Medication Guide to each patient. 30 film-coated tablets PRINCIPAL DISPLAY PANEL - 10 mg/20 mg Tablet Bottle Carton
PRINCIPAL DISPLAY PANEL - 10 mg/40 mg Tablet Bottle Carton NDC 66215-814-30 Rx only Opsynvi ® (macitentan and tadalafil) tablets 10 mg / 40 mg Attention: Dispense the enclosed Medication Guide to each patient. 30 film-coated tablets PRINCIPAL DISPLAY PANEL - 10 mg/40 mg Tablet Bottle Carton
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.Manufactured for: Actelion Pharmaceuticals US, Inc. a Janssen Pharmaceutical Company Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2024 Actelion Pharmaceuticals US, Inc.
OPSYNVI: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity Counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with OPSYNVI and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use reliable methods of contraception while taking OPSYNVI and for one month after discontinuing OPSYNVI [see Use in Specific Populations (8.1) ] . Macitentan-Containing Products REMS For female patients, OPSYNVI is available only through a restricted program called the Macitentan-Containing Products REMS [see Warnings and Precautions (5.2) ] . Male patients are not enrolled in the Macitentan-Containing Products REMS. Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control which is used to ensure that another acceptable form of birth control is selected. Patients should be instructed to contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed. Inform female patients (and their guardians, if applicable) of the following notable requirements. Female patients must sign an enrollment form. Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] . Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber. Review the Medication Guide and REMS educational materials with female patients. Lactation Advise women not to breastfeed during treatment with OPSYNVI [see Use in Specific Populations (8.2) ] . Infertility Advise males of reproductive potential that OPSYNVI may impair fertility [see Warnings and Precautions (5.11) , Clinical Pharmacology (12.2) , Use in Specific Populations (8.3) , and Nonclinical Toxicology (13.1) ]. Hepatotoxicity Some members of this pharmacological class are hepatotoxic. Educate patients on signs of hepatotoxicity. Advise patients that they should contact their doctor if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching. Hemoglobin Decrease Advise patients that they may develop anemia. Advise patients that they will have blood tests to check their red blood cells before starting OPSYNVI. Use with Organic Nitrates or Guanylate Cyclase (GC) Stimulators Inform patients of contraindication of OPSYNVI with any use of organic nitrates or GC stimulators. Vision Loss Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking OPSYNVI. Such an event may be a sign of NAION. Also discuss with patients that there is an increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors. Hearing Loss Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking OPSYNVI. These events may be accompanied by tinnitus and dizziness. Fluid Retention Educate patients on signs of fluid retention. Advise patients that they should contact their doctor if they have unusual weight increase or swelling of the ankles or legs. Administration Patients should be advised not to cut, crush, or chew tablets.
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.MEDICATION GUIDE OPSYNVI ® (op-SIN-vee) (macitentan and tadalafil) tablets This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 03/2024 Read this Medication Guide for OPSYNVI before you start taking OPSYNVI and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about OPSYNVI? Serious birth defects. OPSYNVI can cause serious birth defects if taken during pregnancy. Females must not be pregnant when they start taking OPSYNVI or become pregnant during treatment with OPSYNVI or for 1 month after stopping treatment with OPSYNVI. Females who are able to get pregnant must have a negative pregnancy test before beginning treatment with OPSYNVI, each month during treatment with OPSYNVI and 1 month after stopping OPSYNVI. Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do the pregnancy test and will order a pregnancy test for you depending on your menstrual cycle. Females who are able to get pregnant are females who: have entered puberty, even if they have not started their menstrual period, and have a uterus, and have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who: have not yet entered puberty, or do not have a uterus, or have gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Females who are able to get pregnant must use 2 acceptable forms of birth control during treatment with OPSYNVI, and for 1 month after stopping OPSYNVI because the medicine may still be in the body. If you have had a tubal sterilization, have a progesterone implant, or have an IUD (intrauterine device), these methods can be used without another form of birth control. Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with OPSYNVI. If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control. See the chart below for Acceptable Birth Control Options during treatment with OPSYNVI. Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control. Tell your healthcare provider right away if you miss a menstrual period or think you may be pregnant. Females can only receive OPSYNVI through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS). If you are a female who can get pregnant, you must talk to your healthcare provider, understand the benefits and risks of OPSYNVI, and agree to all of the instructions in the Macitentan-Containing Products REMS. Males can receive OPSYNVI without taking part in the Macitentan-Containing Products REMS. See " What are the possible side effects of OPSYNVI? " for more information about side effects. What is OPSYNVI? OPSYNVI is a prescription medicine that contains 2 medicines called macitentan and tadalafil. OPSYNVI is used for long-term treatment of adults with pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs. It is not known if OPSYNVI is safe and effective in children. Who should not take OPSYNVI? Do not take OPSYNVI if you: are pregnant, plan to become pregnant, or become pregnant during treatment with OPSYNVI. OPSYNVI can cause serious birth defects (see " What is the most important information I should know about OPSYNVI? ") are allergic to macitentan, tadalafil, or any of the ingredients in OPSYNVI. See the end of this Medication Guide for a complete list of ingredients in OPSYNVI. take any medicines called nitrates take any medicines called guanylate cyclase (GC) stimulators Before taking OPSYNVI, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have low blood pressure have anemia have heart problems including heart attack or heart failure have pulmonary veno-occlusive disease (PVOD) have any eye problems, including NAION or an inherited eye disorder called retinitis pigmentosa have hearing problems such as ringing in the ears, dizziness, or loss of hearing have a deformed penis shape or Peyronie's disease or have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia. These conditions increase your risk of getting a prolonged erection. have kidney problems or get dialysis are pregnant or plan to become pregnant during OPSYNVI treatment. OPSYNVI can cause serious birth defects. See " What is the most important information I should know about OPSYNVI? " are breastfeeding or plan to breast feed. It is not known if OPSYNVI passes into your breastmilk. Do not breastfeed during treatment with OPSYNVI. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking OPSYNVI with other medicines may affect the way OPSYNVI and the other medicines work, and may increase your risk of side effects. Do not start any new medicine until you check with your healthcare provider. Especially tell your healthcare provider if you take: nitrate medicines HIV medicines antifungal medicines antiseizure medicines medicines used to treat infection erectile dysfunction medicines blood pressure medicines medicines used to treat PAH or heart problems Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list and show it to your healthcare provider or pharmacist when you get a new medicine. How should I take OPSYNVI? OPSYNVI will be mailed to you by a specialty pharmacy. Your healthcare provider will give you complete details. Take OPSYNVI exactly as your healthcare provider tells you to take it. Do not stop taking OPSYNVI unless your healthcare provider tells you. Take OPSYNVI with or without food. Do not cut, crush, or chew OPSYNVI tablets. If you take too much OPSYNVI, call your healthcare provider or go to the nearest hospital emergency room right away. If you miss a dose of OPSYNVI, take it as soon as you remember that day. Take the next dose at your regular time. Do not take 2 doses at the same time to make up for a missed dose. What should I avoid while taking OPSYNVI? Do not have more than 4 alcohol-containing drinks in a short period of time during treatment with OPSYNVI. Drinking too much alcohol can increase your chances of getting low blood pressure, increased heart rate, dizziness, and headache. What are the possible side effects of OPSYNVI? OPSYNVI can cause serious side effects, including: Serious birth defects. See " What is the most important information I should know about OPSYNVI? " Liver problems . OPSYNVI can cause liver problems. Your healthcare provider should do blood tests to check your liver before you start taking OPSYNVI. Tell your healthcare provider if you have any of the following symptoms of liver problems during treatment with OPSYNVI. nausea or vomiting pain in the upper right stomach tiredness loss of appetite yellowing of your skin or whites of your eyes dark urine fever itching Decreased blood pressure (hypotension). OPSYNVI can cause low blood pressure that lasts for a short time. Low red blood cell levels (anemia) can occur with OPSYNVI treatment, usually during the first weeks after starting therapy. Your healthcare provider will do blood tests to check your red blood cells before starting and as needed during treatment with OPSYNVI. Vision loss. OPSYNVI can cause decreased eyesight or permanent loss of vision in 1 or both eyes, which could be a sign of NAION. There is an increased risk of NAION in people who have already had NAION in 1 eye. If you notice a sudden decrease or loss of vision in 1 or both eyes, contact your healthcare provider right away. Hearing problems. Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness, can happen during treatment with OPSYNVI. If you notice a sudden decrease or loss of hearing, contact your healthcare provider right away. Fluid retention. Fluid retention can happen within weeks after starting OPSYNVI and could lead to hospitalization. Tell your healthcare provider right away if you have any unusual weight gain, trouble breathing, or swelling of your ankles or legs. Your healthcare provider will look for the cause of any fluid retention and may stop treatment with OPSYNVI. Decreased sperm count. OPSYNVI can cause decreased sperm counts in males and may affect the ability to father a child. Tell your healthcare provider if being able to have children is important to you. Prolonged erection. Erections that last more than 4 hours, with or without pain, can happen during treatment with OPSYNVI. Painful erections (priapism) can cause permanent damage to the penis if not treated right away. Tell your healthcare provider right away if you have an erection that lasts longer than 4 hours, with or without pain. The most common side effects of OPSYNVI include: too much fluid in your body (fluid retention) and swelling caused by too much fluid (edema) anemia headache, including migraine headache These are not all the possible side effects of OPSYNVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store OPSYNVI? Store OPSYNVI tablets at room temperature between 68°F to 77°F (20°C to 25°C). Store OPSYNVI in the package that it comes in to protect from moisture. OPSYNVI contains a desiccant to help keep the tablets dry. Do not discard or eat the desiccant. OPSYNVI bottles have a child-resistant cap. Keep OPSYNVI and all medicines out of the reach of children. General information about the safe and effective use of OPSYNVI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use OPSYNVI for a condition for which it was not prescribed. Do not give OPSYNVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about OPSYNVI that is written for health professionals. What are the ingredients in OPSYNVI? Active ingredients: macitentan and tadalafil Inactive ingredients: tablet core: hydroxypropyl cellulose, hydroxypropyl cellulose (low substituted), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, sodium starch glycolate, sodium lauryl sulfate. 10 mg/20 mg film-coating: hydroxypropyl methylcellulose, iron oxide red, iron oxide yellow, lactose monohydrate, talc, titanium dioxide, triacetin. 10 mg/40 mg film-coating: hydroxypropyl methylcellulose, lactose monohydrate, talc, titanium dioxide, triacetin. Manufactured for: Actelion Pharmaceuticals US, Inc. a Janssen Pharmaceutical Company Titusville, NJ 08560, USA For patent information: www.janssenpatents.com For more information, call 1-800-526-7736 (1-800-JANSSEN), or visit www.OPSYNVI.com. © 2024 Actelion Pharmaceuticals US, Inc. Chart
| MEDICATION GUIDE OPSYNVI ® (op-SIN-vee) (macitentan and tadalafil) tablets | |||||
|---|---|---|---|---|---|
| This Medication Guide has been approved by the U.S. Food and Drug Administration. | Issued: 03/2024 | ||||
| Read this Medication Guide for OPSYNVI before you start taking OPSYNVI and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. | |||||
| |||||
| |||||
| |||||
| |||||
|
|
| |||
| Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list and show it to your healthcare provider or pharmacist when you get a new medicine. | |||||
| |||||
| |||||
| |||||
|
| ||||
| |||||
| |||||
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Pulmonary Arterial Hypertension OPSYNVI OPSYNVI was demonstrated to reduce pulmonary vascular resistance (PVR) in a multi-national, multi-center, double-blind, adaptive, randomized, active-controlled, parallel-group study [NCT03904693 (A DUE)] in 187 patients with PAH (WHO FC II–III). The study was designed to compare the efficacy and safety of OPSYNVI to each monotherapy macitentan or tadalafil. Patients with PVR of at least 240 dyn∙s/cm 5 were randomized to receive OPSYNVI (n=108), 10 mg macitentan monotherapy (n=35) or 40 mg tadalafil monotherapy (n=44), once daily. Patients who received treatment during the double-blind treatment period (n=186) were either treatment-naïve (53%) or on an ERA (17%) or a PDE5 inhibitor (30%). Patients enrolled had idiopathic PAH (51%), heritable PAH (5%), PAH associated with connective tissue disease (35%), or PAH associated with congenital heart disease (3%). The mean age was 50 years (range 18–80), 20% of patients were ≥65 years of age, 22% were male and 62% were white. At the time of enrollment, 51% of patients were WHO FC II and 49% were WHO FC III. Patients who were not on a therapeutic PDE5 inhibitor dose at baseline received a 1-week titration period of macitentan 10 mg and tadalafil 20 mg. The primary endpoint of the study was change from baseline in PVR (expressed as the ratio of geometric means of end of double-blind treatment to baseline) vs the individual component monotherapies after 16 weeks. Hemodynamic OPSYNVI demonstrated greater reduction in PVR after 16 weeks. Treatment with OPSYNVI resulted in a statistically significant treatment effect of 0.71 (95% CL 0.61, 0.82, p < 0.0001) representing a 29% reduction in PVR as compared to macitentan, and of 0.72 (95% CLs 0.64, 0.80, p < 0.0001) representing a 28% reduction in PVR as compared to tadalafil (Table 4). Table 4: Change from Baseline in PVR at Week 16 Treatment-naïve and Prior ERA Treatment Treatment-naïve and Prior PDE5 Inhibitor Treatment Macitentan (n=35) OPSYNVI (n=70) Tadalafil (n=44) OPSYNVI (n=86) Baseline mean (SD) 816 (401) 834 (631) 802 (552) 885(640) Reduction at Week 16 (dynes *sec/cm5) Mean (SD) -162 (240) -371 (429) -181 (238) -385 (396) Geometric mean (Week 16/Baseline) 0.77 0.55 0.78 0.56 Treatment effect ratios (95% CL) -29% (-39%, -18%) -28% (-36%, -20%) 2-sided p-value <0.0001 <0.0001 A consistent effect of OPSYNVI on reducing PVR was seen across subgroups of age, sex, race, geographical region, and baseline WHO FC (see Figure 2 ). Additionally, a consistent effect was observed in patients who were either treatment-naïve, or previously exposed to an ERA or PDE5 inhibitor. Figure 2: Subgroup Analysis of the A DUE Study The individual components of OPSYNVI, macitentan and tadalafil, have been approved and used independently or concomitantly in the clinical setting to effectively manage PAH. Macitentan is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH. Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) to improve exercise ability. Figure 2 Macitentan The primary efficacy endpoint of the multi-center, long-term, placebo-controlled SERAPHIN study was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of intravenous or subcutaneous prostanoids, or "other worsening of PAH" during double-blind treatment plus 7 days. Other worsening was defined as all of the following: 1) a sustained ≥15% decrease from baseline in 6-minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and 3) need for additional treatment for PAH. All of these other worsening events were confirmed by an independent adjudication committee, blinded to treatment allocation. Treatment with OPSUMIT 10 mg reduced the risk of clinical worsening events and hospitalization for PAH. Tadalafil The primary efficacy endpoint of a randomized, 16-week placebo-controlled study was the change from baseline at week 16 in 6-minute walk distance. Treatment with tadalafil 40 mg improved exercise ability.
| Treatment-naïve and Prior ERA Treatment | Treatment-naïve and Prior PDE5 Inhibitor Treatment | |||
|---|---|---|---|---|
| Macitentan (n=35) | OPSYNVI (n=70) | Tadalafil (n=44) | OPSYNVI (n=86) | |
| Baseline mean (SD) | 816 (401) | 834 (631) | 802 (552) | 885(640) |
| Reduction at Week 16 (dynes *sec/cm5) Mean (SD) | -162 (240) | -371 (429) | -181 (238) | -385 (396) |
| Geometric mean (Week 16/Baseline) | 0.77 | 0.55 | 0.78 | 0.56 |
| Treatment effect ratios (95% CL) | -29% (-39%, -18%) | -28% (-36%, -20%) | ||
| 2-sided p-value | <0.0001 | <0.0001 | ||
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Of the total number of subjects in the clinical study of OPSYNVI for PAH, 20% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and efficacy of OPSYNVI in children has not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy 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. The available data from OPSYNVI pharmacovigilance reports and published case reports on macitentan are insufficient to evaluate the potential risk of embryo-fetal toxicity. 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed ( 8.2 ) Renal Impairment: Avoid use in patients with creatinine clearance 15–29 mL/min ( 8.6 ) Hepatic Impairment: Do not initiate in patients with severe hepatic impairment ( 8.7 ) 8.1 Pregnancy 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. The available data from OPSYNVI pharmacovigilance reports and published case reports on macitentan are insufficient to evaluate the potential risk of embryo-fetal toxicity. 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. 8.2 Lactation Risk Summary There are no data on the presence of tadalafil, macitentan, and/or their metabolites in human milk, the effects on the breastfed infant, or the effect on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats (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 from OPSYNVI, advise women not to breastfeed during treatment with OPSYNVI. Data Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating OPSYNVI, monthly during treatment and one month after stopping treatment with OPSYNVI. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus [see Dosage and Administration (2.2) and Contraindications (4.1) ]. Contraception Female patients of reproductive potential must use acceptable methods of contraception during treatment with OPSYNVI and for 1 month after treatment with OPSYNVI. Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Warnings and Precautions (5.1) ] . Infertility Males Macitentan Based on findings in animals, macitentan may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warnings and Precautions (5.11) , Clinical Pharmacology (12.2) , and Nonclinical Toxicology (13.1) ]. Tadalafil Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the two studies is unknown. There have been no studies evaluating the effect of tadalafil on fertility in men or women [see Clinical Pharmacology (12.2) and Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and efficacy of OPSYNVI in children has not been established. 8.5 Geriatric Use Of the total number of subjects in the clinical study of OPSYNVI for PAH, 20% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 8.6 Renal Impairment The use of OPSYNVI is not recommended in patients undergoing dialysis. Avoid use of OPSYNVI in patients with severe renal impairment (creatinine clearance 15–29 mL/min) because of increased tadalafil exposure (AUC), lack of clinical experience and the lack of ability to influence clearance by dialysis. For patients with mild (creatinine clearance 51–80 mL/min) to moderate (creatinine clearance 30–50 mL/min) renal impairment, the recommended dose should be consistent with the adult dosing [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment OPSYNVI was not studied in severe hepatic impairment patients defined as a Model for End-Stage Liver Disease score ≥19. OPSYNVI must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the Upper Limit of Normal at baseline (> 3 × ULN). For patients with mild to moderate hepatic impairment (Child Pugh Class A or B) the recommended dose should be consistent with the adult dosing see Dosage and Administration (2.1) [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ].
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING OPSYNVI ® (macitentan and tadalafil) tablets, 10 mg/20 mg, are supplied as pink, oblong film-coated tablets debossed with "1020" on one side and "MT" on the other side. OPSYNVI 10 mg/20 mg is supplied as follows: 7-count bottles with child-resistant closure NDC 66215-812-07 7-count blister NDC 66215-812-08 30-count bottle with child-resistant closure NDC 66215-812-30 OPSYNVI ® (macitentan and tadalafil) tablets, 10 mg/40 mg, are supplied as white to almost-white, oblong film-coated tablets debossed with "1040" on one side and "MT" on the other side. OPSYNVI 10 mg/40 mg is supplied as follows: 10-count blister NDC 66215-814-10 30-count bottle with child-resistant closure NDC 66215-814-30 Store at 20ºC to 25ºC (68ºF to 77ºF); excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature] . Store and dispense in the original package to protect from moisture. Do not discard the desiccant.
Storage and handling
Information about safe storage and handling of the drug product.Store at 20ºC to 25ºC (68ºF to 77ºF); excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature] . Store and dispense in the original package to protect from moisture. Do not discard the desiccant.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: EMBRYO-FETAL TOXICITY Do not administer OPSYNVI to a pregnant female because it may cause fetal harm [see Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1) ]. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception [see Use in Specific Populations (8.3) ]. For all female patients, OPSYNVI is available only through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2) ] . WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Do not administer OPSYNVI to a pregnant female because it may cause fetal harm ( 4.1 , 5.1 , 8.1 ). Females of reproductive potential: exclude pregnancy before start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after treatment by using acceptable methods of contraception ( 2.2 , 8.3 ). For all female patients, OPSYNVI is available only through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) ( 5.2 ).
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API