Macitentan-Tadalafil

Macitentan-Tadalafil is a combination medication indicated for the treatment of pulmonary arterial hypertension (PAH, World Health Organization Group I and WHO Functional Class II-III)

• Macitentan-Tadalafil is available under the following different brand names: Opsynvi.

Common side effects of Macitentan-Tadalafil include:

• too much fluid in the body (fluid retention) and swelling caused by too much fluid (edema)
• anemia
• headache, including migraine headache

Serious side effects of Macitentan-Tadalafil include:

• serious birth defects
• liver problems such as nausea or vomiting, yellowing of the skin or whites of the eyes, pain in the upper right stomach, dark urine, tiredness, fever, loss of appetite, itching
• decreased blood pressure (hypotension)
• anemia
• vision loss
• hearing problems
• fluid retention
• decreased sperm count
• prolonged erection

Rare side effects of Macitentan-Tadalafil include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Pulmonary arterial hypertension

• Treatment-naïve to any PAH therapy or transitioning from ERA monotherapy
• One 10 mg/20 mg tablet orally once a day
• If tolerated, titrate upward to one 10 mg/40 mg tablet orally once a day
• Transitioning from PDE5 inhibitor monotherapy or PDE5 inhibitor and ERA therapy in combination
• One 10 mg/40 mg tablet orally once a day

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

Macitentan-Tadalafil has severe interactions with the following drugs:

• isosorbide dinitrate
• isosorbide mononitrate
• nitroglycerin IV
• nitroglycerin PO
• nitroglycerin rectal
• nitroglycerin sublingual
• nitroglycerin topical
• nitroglycerin transdermal
• nitroglycerin translingual
• riociguat
• sparsentan
• vericiguat

Macitentan-Tadalafil has serious interactions with at least 63 other drugs

Macitentan-Tadalafil has moderate interactions with at least 160 other drugs

Macitentan-Tadalafil has minor interactions with the following drugs:

• acetazolamide
• anastrozole
• cyclophosphamide
• danazol
• drospirenone
• larotrectinib
• nirmatrelvir/ritonavir
• ranolazine
• sildenafil

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• History of hypersensitivity reaction to drugs or excipients
• Pregnancy; consistently shown to have teratogenic effects in animal studies
• Guanylate cyclase (GC) stimulators (eg,  riociguat); tadalafil may potentiate hypotensive effects of GC stimulators
• Coadministration of tadalafil with nitrates (either regularly and/or intermittently) and nitric oxide donors

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Macitentan-Tadalafil?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Macitentan-Tadalafil?”

Cautions

• May cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant
• For all women, Macitentan-Tadalafil is available only through a restricted program called the macitentan-containing products risk evaluation and mitigation strategy (REMS)
• Hepatotoxicity
  • Endothelin receptor antagonists (ERAs) have caused elevations of aminotransferases, hepatotoxicity, and liver failure
  • Obtain liver enzyme tests before initiating and repeat during treatment as clinically indicated; do not initiate if aminotransferases more than 3 x ULN
  • Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching)
  • Discontinue drug if clinically relevant aminotransferase elevations occur, or if elevations are accompanied by increased bilirubin more than 2 x ULN, or by clinical symptoms of hepatotoxicity
  • Consider reinitiating when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity
• Hypotension
  • Tadalafil vasodilatory properties may result in transient decreases in blood pressure (BP)
  • Before initiating, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects
  • Patients with preexisting hypotension, autonomic dysfunction, with left ventricular outflow obstruction, may be particularly sensitive to vasodilator actions
• Decreased hemoglobin
  • Decreases in hemoglobin seldom require transfusion
  • Do not initiate drug in patients with severe anemia
  • Measure hemoglobin before initiating and repeat during treatment as clinically indicated
  • Worsening pulmonary veno-occlusive disease (PVOD)
  • Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD)
  • Use is not recommended in patients with PVOD
  • If signs of pulmonary edema occur, consider the possibility of associated PVOD; if confirmed, discontinue the drug
• Visual loss
  • Nonarthritic 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 phosphodiesterase 5 (PDE5) inhibitors
  • Most, but not all, cases had underlying anatomic or vascular risk factors for the development of NAION, including low cup-to-disc ratio (“crowded disc”), age above 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, smoking
  • Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in clinical trials; Macitentan-Tadalafil is not recommended in these patients
• Hearing impairment
  • Sudden decrease or loss of hearing, which may include tinnitus and dizziness, reported with tadalafil
  • It is not possible to determine if the etiology is related directly to PDE5 inhibitor use or other factors
• Fluid retention
  • Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs and heart failure have been reported in patients taking Macitentan-Tadalafil
  • Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment
  • Monitor for signs of fluid retention after initiating; if significant fluid retention develops, determine the cause, such as macitentan or underlying heart failure, and the possible need to discontinue the drug
• Decreased sperm count
  • Macitentan, like other ERAs, may hurt spermatogenesis
  • Counsel men about potential effects on fertility
• Prolonged erection
  • Prolonged erections of more than 4 hours and priapism (painful erections more than 6 hours in duration) were reported for PDE5 inhibitors
  • Patients with conditions that might predispose them to priapism (eg, sickle cell anemia, multiple myeloma, or leukemia), or anatomical deformation of the penis (eg, angulation, cavernosal fibrosis, Peyronie disease) are at an increased risk
  • If not treated promptly, priapism can result in irreversible damage to the erectile tissue
  • Instruct patients who have an erection lasting more than 4 hours, whether painful or not, to seek emergency medical attention
• Drug interaction overview
  • Macitentan is a substrate of CYP3A4 and CYP2C9
  • Nitrates
    • Contraindicated
• Administration of nitrates within 48 hours after the last dose of Macitentan-Tadalafil is contraindicated
• Tadalafil and nitrates may cause additive hypotensive effects if coadministered
• Guanylate cyclase (GC) stimulators
  • Contraindicated
  • Tadalafil and GC stimulators (eg, riociguat, vericiguat) may cause additive hypotensive effects if coadministered
  • Strong CYP3A4 inducers
    • Avoid
  • Strong CYP3A4 inducers significantly reduce macitentan and tadalafil systemic exposure
  • Strong CYP3A4 inhibitors
    • Avoid
  • Strong CYP3A4 inhibitors significantly increase macitentan and tadalafil systemic exposure
  • Moderate dual or combined CYP3A4 and CYP2C9 inhibitors
    • Avoid
  • Coadministration of moderate dual inhibitors of CYP3A4 and CYP2C9 (eg, fluconazole, amiodarone) is predicted to increase macitentan exposure approximately 4-fold
  • Use other PAH treatment options when strong CYP3A4 inhibitors are needed
  • Other PDE5 inhibitors
  • Avoid coadministration
  • Tadalafil is also indicated for erectile dysfunction
• Instruct patients not to take other PDE5 inhibitors (eg, avanafil, sildenafil, vardenafil) while taking tadalafil
• Alpha blockers
  • Avoid
• PDE5 inhibitors (eg, Tadalafil) and alpha-adrenergic blocking agents are both vasodilators with BP-lowering effects
• Antihypertensives
  • Caution, monitor
  • PDE5 inhibitors are mild systemic vasodilators; small reductions in BP occurred in clinical trials when coadministered with antihypertensive agents
• Alcohol
  • Caution, monitor
• Both alcohol and PDE5 inhibitors act as mild vasodilators
• Substantial consumption of alcohol in combination with macitentan can increase the potential for orthostatic signs and symptoms, including increased heart rate, decreased standing BP, dizziness, and headache

Pregnancy and Lactation

• Based on data from animal reproduction studies, Macitentan is contraindicated during pregnancy owing to embryo-fetal toxicity, including birth defects and fetal death
• Pregnancy testing required
  • Verify pregnancy status of women of reproductive potential before initiating, monthly during treatment, and 1 month after stopping treatment
  • Instruct patient to contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy suspected
  • If the pregnancy test is positive, discuss the risks to the patient, the pregnancy, and the fetus
• Clinical considerations
  • 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
• Contraception
  • Women patients of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after treatment discontinued
  • Patients may choose 1 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 2 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 counselling by another healthcare provider trained in contraceptive counselling
• Infertility in males
• Macitentan
  • Based on findings in animals, macitentan may impair fertility in males of reproductive potential
  • Unknown whether effects on fertility are reversible
• Tadalafil
  • Tadalafil decreased sperm concentrations for 6-9 months in 2 clinical trials
  • No adverse effects observed on mean concentrations of testosterone, luteinizing hormone, or follicle-stimulating hormone
  • The clinical significance of decreased sperm concentrations in the 2 studies is unknown
• Lactation
  • Data are unavailable on the presence of Tadalafil, Macitentan, and/or their metabolites in human milk, effects on breastfed infants, or on milk production
  • Tadalafil and/or its metabolites are present in the milk of lactating rats; when a drug is present in animal milk, it is likely to be present in human milk
  • Because of the potential for serious adverse reactions, advise women not to breastfeed during treatment