Opsynvi Special Precautions

Hepatotoxicity: ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure.
The incidence of elevated aminotransferases in the double-blind and combined double-blind (DB)/open-label (OL) arms of the study of OPSYNVI in PAH are shown in Table 2. (See Table 2.)

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The overall incidence of treatment discontinuations for hepatic adverse events in the double-blind and combined double-blind/open-label arms study of OPSYNVI in PAH data were 0.9% and 2.2% respectively.
The incidence of elevated aminotransferases in the study of OPSUMIT (macitentan) in PAH is shown in Table 3. (See Table 3.)

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In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events were 3.3% in the OPSUMIT 10 mg group vs. 1.6% for placebo.
Obtain liver enzyme tests prior to initiation of OPSYNVI and repeat during treatment as clinically indicated.
Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSYNVI. Consider re-initiation of OPSYNVI when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
Do not initiate OPSYNVI in patients with elevated aminotransferases (> 3x upper limit of normal [ULN]) at baseline. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, and, therefore, avoid use of OPSYNVI.
Hypotension: OPSYNVI tablets have vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing OPSYNVI tablets, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with pre-existing hypotension, with autonomic dysfunction, with left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators [see Pharmacology: Pharmacodynamics under Actions].
Hemoglobin Decrease: Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSYNVI and OPSUMIT. These decreases occurred early and stabilized thereafter.
In the placebo-controlled study of OPSUMIT in PAH, OPSUMIT 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT 10 mg group and in 3.4% of the placebo group. Similar results were observed in the trial with OPSYNVI.
Decreases in hemoglobin seldom require transfusion. Initiation of OPSYNVI is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated [see Clinical Trials Experience under Adverse Reactions].
Worsening Pulmonary Veno-Occlusive Disease (PVOD): Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of OPSYNVI tablets to patients with veno-occlusive disease, administration of OPSYNVI tablets to such patients is not recommended. Should signs of pulmonary edema occur when OPSYNVI tablets are administered, the possibility of associated PVOD should be considered. If confirmed, discontinue OPSYNVI.
Visual Loss: Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, has been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged greater than or equal to 50 in the general population. Other risk factors for NAION, such as the presence of "crowded" optic disc, may have contributed to the occurrence of NAION.
Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use of OPSYNVI in these patients is not recommended.
Hearing Impairment: Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
Fluid Retention: Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs and heart failure has been reported in patients taking OPSYNVI. In the active-controlled and combined double-blind/open-label arms of the study of OPSYNVI in PAH, the incidence of peripheral edema/fluid retention was 20.6% in the active- controlled and 17.3% in the double-blind/open-label arm [see Clinical Trials Experience under Adverse Reactions]. In the placebo-controlled study of OPSUMIT in PAH, the incidence of edema was 21.9% in the OPSUMIT 10 mg group and 20.5% in the placebo group.
Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. In a small study of OPSUMIT in patients with pulmonary hypertension because of left ventricular dysfunction, more patients in the OPSUMIT group developed significant fluid retention and had more hospitalizations because of worsening heart failure compared to those randomized to placebo. Postmarketing cases of edema and fluid retention occurring within weeks of starting OPSUMIT, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported.
Monitor for signs of fluid retention after OPSYNVI initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as OPSYNVI or underlying heart failure, and the possible need to discontinue OPSYNVI.
Combination with Other PDE5 Inhibitors: Tadalafil is also indicated for erectile dysfunction. The safety and efficacy of taking tadalafil tablets together with another PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Instruct patients taking OPSYNVI tablets not to take other PDE5 inhibitors.
Decreased Sperm Count: Macitentan, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility [see Use in Pregnancy & Lactation and Pharmacology: Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].
Prolonged Erection: There have been reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors like tadalafil. Patients with conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) are at an increased risk. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.
Effects on ability to drive and use machine: No studies on the effect of OPSYNVI on the ability to drive and use machines have been performed. However, as OPSYNVI contains macitentan and tadalafil, the patient should be informed of the individual component data before driving vehicles or operating machinery.
Use in Pregnancy: Embryo-fetal Toxicity: Based on data from animal reproduction studies, OPSYNVI may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. The available human data for ERAs do not establish the presence or absence of major birth defects related to the use of OPSYNVI. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test prior to initiation of therapy with OPSYNVI. Advise patients who can become pregnant to use effective contraceptive methods prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with OPSYNVI. When pregnancy is detected, discontinue use as soon as possible [see Pregnancy Testing in Females of Reproductive Potential under Dosage & Administration, Use in Pregnancy under Contraindications, and Use in Pregnancy & Lactation].