Both medications work to decrease blood pressure in lung arteries but in different ways.

Macitentan blocks endothelin, a substance made by the body that causes blood vessels in the arteries of the lungs to constrict. Endothelin causes abnormal growth of the muscular layer in the vessel wall, which narrows the lumen, or space inside the blood vessel. People with PH sometimes produce too much endothelin.

This narrowing causes the pressure to increase, making it harder for the right side of the heart to push the blood through the lungs to get oxygen. By blocking the action of endothelin, ambrisentan helps relax the blood vessels so the lung blood pressure goes down. Lower lung pressures reduce stress on the right heart so heart function improves. Improved heart function generally allows people to be more active, as shown by research studies.

Tadalafil blocks the action of an enzyme known as phosphodiesterase-5 (PDE-5). This enzyme breaks down a substance called cyclic guanosine monophosphate (cGMP) that causes smooth muscles to relax. By blocking PDE-5 in people with PAH, cGMP within the smooth muscles promotes muscle relaxation and widening of blood vessels in the arteries of the lungs. The muscle relaxation allows the right side of the heart to pump blood through the lungs more easily.

Take one tablet by mouth once daily with or without food.

Swallow tablet whole with water. Don’t cut, crush or chew tablets.

Macitentan and tadalafil combination tablet is available in two strengths:

• Macitentan 10 mg and tadalafil 20 mg
• Macitentan 10 mg and tadalafil 40 mg tablet

For patients who have never received PAH treatment, the recommended starting dose is one 10 mg/20 mg tablet once daily for one week, then increase to one 10 mg/40 mg tablet once daily.

For patients who have been on a PDE5 inhibitor alone, or PDE5 inhibitor plus an endothelin receptor antagonist,, the recommended dose is one 10 mg/40 mg tablet once daily.

Macitentan/tadalafil combination tablet has limited distribution, which means you can’t fill the prescription at a local pharmacy. A specialty pharmacy specified by your insurance plan will ship the medicine to you. You might need approval from your insurance company before starting therapy.  

Due to the risk of serious birth defects, women of reproductive potential must comply with monthly pregnancy testing and contraception requirements.

The most common side effects of this medication are:

• Fluid retention (too much fluid in your body) and edema (swelling caused by too much fluid)
• Anemia (a condition in which blood doesn’t have enough healthy red blood cells and hemoglobin to carry oxygen through the body)
• Headache, including migraines

More serious side effects include:

Serious birth defects: Because of the potential harm to the fetus, women of childbearing potential have pregnancy tests before starting therapy and every month while they are taking macitentan/tadalafil combination tablet.

Low blood pressure that lasts for a short period of time.

Liver problems: Liver problems can occur with ERAs like macitentan. Liver problems can occur with ERAs like macitentan. Your health care provider will test your liver function before starting therapy and routinely during therapy. Your doctor will guide you in managing elevated liver enzymes if you show signs and symptoms of abnormal liver function or injury or your total bilirubin has increased to twice the normal level (as shown on a liver function blood test). In some cases, the doctors will stop the medication.

Anemia: Low red blood cell levels can occur in the first weeks after starting therapy. Your doctor will check your red blood cell count before you start macitentan/tadalafil therapy and periodically thereafter.

Vision loss: Although very rare, PDE5 inhibitors like tadalafil have been linked to sudden vision loss in one or both eyes. Sudden vision loss could indicate serious dysfunction of the optic nerve and requires immediate attention.

Hearing loss: PDE5 inhibitors like tadalafil also have been linked to sudden hearing loss or decreased hearing, sometimes with ringing in the ears and dizziness. If this occurs, seek prompt medical attention.

Fluid retention: Fluid retention is a known side effect of ERAs like macitentan. You might need to reduce salt and fluid in your diet and take a diuretic. The diuretic will help move fluid through the kidneys, causing frequent urination. It is important to notify your physician if you experience swelling or other side effects.

Sperm count changes: Sperm production could change, as observed in animal studies. Men should discuss this with their health care providers.

Prolonged erection: Men could experience prolonged erections (greater than four hours), with or without pain. If you experience this rare but very serious condition, contact your healthcare provider right away.

Certain patient populations must take precautions while taking this medication, while others should avoid it. Learn about who can and who shouldn’t take this combination tablet:

Pregnant and breastfeeding patients: Macitentan/tadalafil combination tablet should not be used during pregnancy. Macitentan has caused birth defects in animal studies.

Women taking macitentan/tadalafil combination tablet shouldn’t become pregnant. Women of childbearing age must use two acceptable methods of contraception while on this therapy, such as tubal ligation, or a copper T380A or LNg 20 intrauterine device.

Women who become pregnant while taking macitentan/tadalafil combination tablet should immediately notify their health care provider and stop taking the medication.

It isn’t known whether macitentan passes into breast milk, so nursing mothers shouldn’t take macitentan/tadalafil combination therapy.

Children and teens: There hasn’t been enough research to determine whether macitentan is safe or effective for children, although research is ongoing.

People with liver disease: Macitentan/tadalafil combination tablet isn’t recommended for people with significant liver disease.

People with kidney disease: For people with mild to moderate kidney disease (creatinine clearance 31 to 80 ml/min), it isn’t necessary to adjust your dose. However, people with moderate kidney disease may be at higher risk for decreased blood pressure (hypotension) and anemia. Macitentan/tadalafil combination tablet isn’t recommended for people with severe kidney disease. It hasn’t been studied in people on dialysis.

Allergic reaction: Allergies are possible but not likely with this medication. Any medication can cause side effects or sensitivities. Check with your doctor if you experience a rash or throat tightening.

Tell your doctor what medications you take, including over-the-counter medicine and herbal supplements to avoid drug interactions. Be especially mindful of these serious interactions:

Don’t take nitrate medicines in any form while taking the macitentan/tadalafil combination tablet. Taking nitrates with tadalafil can cause your systemic blood pressure to fall to unsafe levels. Use caution when taking the macitentan/tadalafil combination tablet with other medications that lower blood pressure, as well as alcohol.

An enzyme called CYP3A breaks down macitentan and tadalafil in the liver. This medication can cause significant interactions with drugs that target this enzyme pathway, such as ketoconazole (for fungal infections), ritonavir (for HIV/AIDS) and rifampin (for tuberculosis).