Brand name: Opsynvi
Drug class: Endothelin receptor antagonists

Medically reviewed by Drugs.com on Feb 10, 2025. Written by ASHP.

Introduction

Fixed combination of macitentan (an endothelin receptor antagonist [ERA] and tadalafil (a phosphodiesterase type 5 [PDE5] inhibitor).

Uses for Macitentan and Tadalafil

Pulmonary Arterial Hypertension

Chronic treatment of pulmonary arterial hypertension (PAH; WHO Group 1) in adults with WHO functional class II–III. Macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability.

Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with established PAH-specific medications. Endothelin-receptor antagonists such as macitentan and PDE5 inhibitors such as tadalafil are recommended among several options for treatment of WHO/NYHA class II or III PAH. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.

Initial oral combination therapy with ambrisentan/tadalafil or macitentan/tadalafil is recommended by some experts in patients with idiopathic, heritable, or drug-associated PAH without cardiopulmonary comorbidities.

Macitentan and Tadalafil Dosage and Administration

General

Pretreatment Screening

• Verify pregnancy status in females of reproductive potential. Initiate treatment in females of reproductive potential only after a negative pregnancy test.

• Obtain liver enzyme tests. Do not initiate therapy in patients with elevated aminotransferases (>3 x ULN) at baseline.

• Obtain hemoglobin concentrations.

Patient Monitoring

• In females of reproductive potential, obtain a pregnancy test monthly during macitentan/tadalafil treatment and 1 month after stopping therapy.

• Monitor for symptoms suggestive of hepatic injury (e.g., nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, itching).

• Obtain liver enzyme tests during treatment as clinically indicated.

• Monitor hemoglobin concentrations during treatment as clinically indicated.

• Monitor for signs of fluid retention.

REMS

• Because of the risk of embryofetal toxicity, female patients can only receive macitentan/tadalafil through a restricted program called the Macitentan-containing Products Risk Evaluation and Mitigation Strategy (REMS).

• All female patients regardless of childbearing potential must enroll in the program prior to initiating macitentan/tadalafil therapy; in addition, females of childbearing potential must comply with all pregnancy testing and contraception requirements of the program. Male patients are exempt from these restrictions and do not need to enroll in the program.

• Prescribers and pharmacies must be certified with the REMS Program. Pharmacies must only dispense to authorized patients.

• Additional information is available at [Web] or 1-888-572-2934.

Administration

Oral Administration

Administer orally once daily with or without food.

Swallow tablets whole with water; do not cut, crush, or chew tablets.

If a dose is missed, take the missed dose as soon as possible and then resume regular schedule; do not take double doses.

Dosage

Adults

PAH

Treatment-naïve Patients or Patients Transitioning from ERA Monotherapy

Oral

Recommended initial dosage is 1 tablet containing macitentan 10 mg and tadalafil 20 mg once daily for 1 week; if tolerated, titrate to 1 tablet containing macitentan 10 mg/tadalafil 40 mg once daily as maintenance dosage.

Patients Transitioning from PDE5 Inhibitor Monotherapy or PDE5 Inhibitor and ERA Combination Therapy

Oral

Recommended dosage is 1 tablet containing macitentan 10 mg and tadalafil 40 mg once daily.

Special Populations

Hepatic Impairment

No dosage change necessary in patients with mild to moderate hepatic impairment (Child Pugh Class A or B); usual adult dosage recommended.

Do not initiate in patients with severe hepatic impairment or clinically significant elevated hepatic aminotransferases (>3 × ULN).

Renal Impairment

No specific change necessary inpatients with mild (Cl_cr 51–80 mL/minute) to moderate (Cl_cr30–50 mL/minute) renal impairment; usual adult dosage recommended.

Avoid use in patients with severe renal impairment (Cl_cr 15–29 mL/minute).

Not recommended in patients undergoing dialysis.

Geriatric Patients

No specific dosage recommendations.

Cautions for Macitentan and Tadalafil

Contraindications

• Pregnancy.

• Hypersensitivity.

• Concomitant use of organic nitrates.

• Concomitant use of guanylate cyclase (GC) stimulators.

Warnings/Precautions

Warnings

Embryo-fetal Toxicity

May cause fetal harm; contraindicated in females who are pregnant. (See Boxed Warning.)

Available for females only through the Macitentan-Containing Products REMS, a restricted distribution program. (See REMS under Dosage and Administration.)

In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.

Other Warnings and Precautions

Hepatotoxicity

ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure.

Obtain liver enzyme tests prior to initiation of therapy and repeat during treatment as clinically indicated.

Monitor for symptoms of hepatic injury (e.g., nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, itching).

If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue macitentan/tadalafil. Consider re-initiation of therapy when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

Do not initiate macitentan/tadalafil in patients with elevated aminotransferases (>3 × ULN) at baseline.

Patients with severe hepatic cirrhosis (Child-Pugh Class C) not studied; avoid use in such patients.

Hypotension

Vasodilatory properties of macitentan/tadalafil may result in transient decreases in BP. Consider whether patients with underlying cardiovascular disease could be adversely affected by such vasodilatory effects. Patients with pre-existing hypotension, autonomic dysfunction, or left ventricular outflow obstruction may be particularly sensitive.

Hemoglobin Decrease

Decreases in hemoglobin concentration and hematocrit observed with macitentan/tadalafil and single-entity macitentan. These decreases occurred early and stabilized thereafter. Rarely required transfusion.

Do not initiate therapy in patients with severe anemia. Measure hemoglobin concentrations prior to initiation and repeat during treatment as clinically indicated.

Pulmonary Veno-occlusive Disease

Pulmonary vasodilators may significantly worsen cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD).

Use of macitentan/tadalafil not recommended in patients with veno-occlusive disease. If signs of pulmonary edema occur, consider possibility of associated PVOD; if confirmed, discontinue macitentan/tadalafil.

Vision Loss

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision and possible permanent vision loss, reported during postmarketing experience in temporal association with the use of PDE5 inhibitors.

Use of macitentan/tadalafil not recommended in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa.

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.

Fluid Retention

Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs; heart failure has been reported in patients taking macitentan/tadalafil.

Monitor for signs of fluid retention. If clinically significant fluid retention develops, evaluate the cause and possible need to discontinue the fixed combination therapy.

Concomitant Use with Other PDE5 Inhibitors

Safety and efficacy of taking tadalafil with another PDE5 inhibitor or other treatments for erectile dysfunction not studied. Do not take macitentan/tadalafil with other PDE5 inhibitors.

Decreased Sperm Count

Reduced sperm counts observed. Counsel men about potential effects on fertility.

Prolonged Erection

Possible prolonged erections (>4 hours) and priapism (painful erections >6 hours in duration) in patients taking PDE5 inhibitors.

Patients with conditions that might predispose them to priapism or patients with anatomical deformation of the penis are at increased risk.

Advise patients to seek emergency medical attention if they experience an erection lasting longer than 4 hours, whether painful or not.

Use of Fixed Combinations

When the fixed combination of macitentan/tadalafil is used, consider the cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.

Specific Populations

Pregnancy

Based on animal data, macitentan/tadalafil is contraindicated during pregnancy. May cause fetal risk. (See Boxed Warning.) Advise pregnant women of the potential risk to a fetus.

Pregnant women with untreated PAH at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.

Consider increased risk of pregnancy-associated maternal and fetal morbidity and mortality in patients with PAH.

Lactation

Not known whether macitentan/tadalafil and their metabolites are present in human milk or if the drugs have any effects on the breastfed infant or on milk production. Tadalafil and/or its metabolites are present in rat milk. Advise women not to breastfed during treatment with macitentan/tadalafil.

Females and Males of Reproductive Potential

Exclude pregnancy in females of childbearing potential prior to initiation and prevent thereafter with acceptable methods of contraception during and for 1 month following cessation of therapy. Monthly pregnancy tests required in females of childbearing potential. If used during pregnancy or if patient becomes pregnant during therapy, apprise patient of potential hazard to fetus.

Counsel patients on pregnancy planning and prevention.

Macitentan may impair fertility in males of reproductive potential. No data on effect of tadalafil on fertility in men or women.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No differences in safety or effectiveness in geriatric patients compared with younger adults.

Hepatic Impairment

Not studied in patients with severe hepatic impairment (defined as a Model for End-Stage Liver Disease score ≥19).

Renal Impairment

Not recommended in patents undergoing dialysis. Avoid use in patients with severe renal impairment (Cl_cr 15–29 mL/minute).

Common Adverse Effects

Most common adverse reactions (≥10%): edema/fluid retention, anemia, headache/migraine.

Drug Interactions

Macitentan is metabolized to its active metabolite primarily by CYP3A4, with minor contributions from CYP2C8, CYP2C9, and CYP2C19.

Macitentan and its active metabolite do not inhibit or induce 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).

Tadalafil is a substrate of CYP3A.

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medications metabolized by CYP isoforms.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 inducers (e.g., rifampin): shown to reduce exposure to macitentan; avoid concomitant use with macitentan/tadalafil.

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir): shown to double macitentan exposure; avoid concomitant use with macitentan/tadalafil.

Moderate dual or combined CYP3A4 and CYP2C9 inhibitors (e.g., fluconazole): predicted to increase macitentan exposure by approximately 4-fold without relevant effect on the exposure to its active metabolite; avoid concomitant use with macitentan/tadalafil.

Specific Drugs

Macitentan and Tadalafil Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentration of macitentan and tadalafil are about 10 hours and 3 hours, respectively. Maximum bioavailability is unknown.

Food

After a high fat breakfast, exposure to macitentan and its active metabolite was unchanged. Food does not substantially alter the rate and extent of absorption of tadalafil and macitentan/tadalafil.

Distribution

Plasma Protein Binding

Macitentan and its active metabolite: >99%

Tadalafil: 94%

Elimination

Metabolism

Macitentan is primarily metabolized by CYP3A4 with minor contributions by CYP2C8, CYP2C9, and CYP2C19 to form the active metabolite. Systemic exposure of the active metabolite is 3-times the exposure to macitentan and contributes to approximately 40% of the total pharmacologic activity.

Tadalafil is metabolized by CYP3A to an inactive catechol metabolite.

Elimination Route

Elimination of macitentan is approximately 50% in urine and 24% in feces. Elimination of tadalafil is predominantly as metabolites and excreted in feces (approximately 61%) and urine (approximately 36%).

Half-life

Elimination half-lives of macitentan and its metabolite are approximately 16 and 48 hours, respectively. Half-life of tadalafil is 11 hours.

Special Populations

Pharmacokinetics of tadalafil may be altered in patients with diabetes mellitus. No clinically relevant effects of race or gender on macitentan, its active metabolite, or tadalafil.

Stability

Storage

Oral

Tablets

Store at 20–25ºC (excursions permitted between 15–30ºC). Store and dispense in original package to protect from moisture. Do not discard the desiccant.

Actions

• Combination of macitentan (an endothelin receptor antagonist) and tadalafil (a PDE5 inhibitor).

• Macitentan is a nonselective (dual receptor) endothelin-1 (ET-1) receptor antagonist that acts on both ET-1 type A and type B receptors; binds with sustained and high affinity to these receptors in pulmonary arterial smooth muscle cells.

• ET-1 is a potent vasoconstrictor and mediator of a variety of deleterious effects (e.g., fibrosis, proliferation, hypertrophy, inflammation); increased concentrations detected in plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disorder.

• Tadalafil is a selective inhibitor of PDE, with greatest selectivity for PDE5, the principal isoenzyme involved in the metabolism of cGMP to GMP in the vascular smooth muscle, smooth muscle of the pulmonary vasculature, prostate, bladder, and corpora cavernosa of the penis. Induces relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with macitentan/tadalafil and for 1 month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests.

• For female patients, macitentan/tadalafil is available only through a restricted program called the Macitentan-Containing Products REMS. Male patients are not enrolled in the REMS program.

• Patients should be instructed to contact their physician if they suspect they may be pregnant. 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 to ensure that another acceptable form of birth control is selected.

• Inform female patients (and their guardians, if applicable) that they must sign an enrollment form. Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements.

• 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.

• Advise women not to breastfeed during treatment with macitentan/tadalafil.

• Advise males of reproductive potential that macitentan/tadalafil may impair fertility.

• 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.

• Advise patients that they may develop anemia. Advise patients that they will have blood tests to check their red blood cells before starting macitentan/tadalafil.

• Inform patients that macitentan/tadalafil is contraindicated with any use of organic nitrates or guanylate cyclase (GC) stimulators.

• Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking macitentan/tadalafil. Such an event may be a sign of NAION. Also, inform 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.

• 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.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of macitentan/tadalafil is restricted in female patients. (See REMS under Dosage and Administration.) Information on Macitentan-Containing Products REMS certified pharmacies or wholesale distributors is available at 1-888-572-2934.

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