OPSYNVI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for OPSYNVI (OPSYNVI).
OPSYNVI is a dual endothelin receptor antagonist (ERA) and phosphodiesterase-5 (PDE5) inhibitor. Macitentan blocks endothelin-1 (ET-1) receptors (ETA and ETB), reducing vasoconstriction and proliferation. Tadalafil inhibits PDE5, increasing cGMP levels and causing vasodilation.
| Metabolism | Macitentan is primarily metabolized by CYP3A4 to its active metabolite (ACT-132577). Tadalafil is primarily metabolized by CYP3A4. |
| Excretion | Primarily fecal (approximately 66% of absorbed dose) and renal (approximately 22% as unchanged drug and metabolites). Biliary excretion is negligible. |
| Half-life | Terminal elimination half-life approximately 15 hours (range 10–20 hours) in patients with pulmonary arterial hypertension; supports twice-daily dosing. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) approximately 50 L (0.7 L/kg for a 70 kg individual), indicating extensive tissue distribution. |
| Bioavailability | Absolute oral bioavailability not determined; relative absorption rapid with Tmax 2–4 hours; food reduces Cmax and AUC by approximately 30% and 20%, respectively. |
| Onset of Action | Oral: Peak plasma concentration at 2–4 hours; clinical effect (6-minute walk distance improvement) observed at week 4 in clinical trials. |
| Duration of Action | Duration of hemodynamic effect approximately 12 hours with twice-daily dosing; sustained efficacy on exercise capacity and functional class over 24 weeks in pivotal trials. |
10 mg orally once daily, in combination with tadalafil 20 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. Not recommended for GFR <30 mL/min due to lack of data. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: not recommended; Child-Pugh C: contraindicated. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment recommended, but consider age-related renal and hepatic function decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for OPSYNVI (OPSYNVI).
| Breastfeeding | No data on presence in human milk. Macitentan and tadalafil are likely excreted in rat milk. M/P ratio unknown. Due to potential serious adverse reactions in nursing infants (e.g., hypotension, teratogenicity), breastfeeding is not recommended during treatment. |
| Teratogenic Risk | Pregnancy Category X: OPSYNVI (macitentan and tadalafil) is contraindicated in pregnancy. Macitentan is an endothelin receptor antagonist associated with teratogenicity including craniofacial, cardiovascular, and neural tube defects in animal studies. Tadalafil may cause fetal harm based on PDE5 inhibitor class effects. Risk is highest during the first trimester (organogenesis). Use effective contraception during treatment and for 1 month after discontinuation. |
■ FDA Black Box Warning
WARNING: EMBRYO-FETAL TOXICITY - Must not be used in pregnant women because it may cause fetal harm (including birth defects and fetal death). Pregnancy must be excluded prior to initiation, and females of reproductive potential must use reliable contraception during treatment and for at least 30 days after stopping.
| Serious Effects |
["Pregnancy","Females of reproductive potential not using contraception","Prior hypersensitivity to macitentan, tadalafil, or any component of OPSYNVI","Concomitant use of organic nitrates (due to tadalafil component)","Concomitant use of guanylate cyclase stimulators (e.g., riociguat) (due to tadalafil component)","Severe hepatic impairment (Child-Pugh Class C)"]
| Precautions | ["Hepatotoxicity: Elevations of liver aminotransferases may occur; monitor liver tests before and during treatment.","Fluid retention: May occur, especially in patients with underlying heart failure.","Hypotension: May cause decrease in blood pressure; monitor closely.","Use with strong CYP3A4 inducers (e.g., rifampin) may reduce efficacy; avoid concomitant use.","Use with strong CYP3A4 inhibitors (e.g., ketoconazole) may increase exposure; consider dose adjustment.","Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider possibility of PVOD."] |
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| Fetal Monitoring | Pre-treatment pregnancy test required. Monthly pregnancy tests during treatment and 1 month after discontinuation. Monitor liver function (ALT, AST) monthly due to macitentan hepatotoxicity. Monitor blood pressure and signs of fluid retention (weight, edema) due to PDE5 inhibitor vasodilation. Fetal ultrasound for potential anomalies if accidental exposure occurs. |
| Fertility Effects | Based on animal studies, OPSYNVI may impair fertility. Macitentan has shown reduced spermatogenesis and testicular tubular atrophy in male rats. Tadalafil may transiently decrease sperm concentration and motility. Reversible upon discontinuation. Clinical significance in humans unknown. |