Macitentan

Macitentan is used to manage the symptoms of pulmonary arterial hypertension (PAH; high blood pressure in the vessels that carry blood to the lungs). Macitentan is in a class of medications called endothelin receptor antagonists. It works by stopping the action of endothelin, a natural substance that causes blood vessels to narrow and prevents normal blood flow in people who have PAH.

Vasodilator; an endothelin-receptor antagonist.1 7 8 9 10 11

• 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.1 6 10 19 20

• 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.1 4 8 20 23 40

• Differs from other endothelin-receptor antagonists in ET-1 receptor selectivity; clinical importance of selective versus nonselective endothelin receptor blockade not known.6 9 10 22 40

• Improves hemodynamics (e.g., pulmonary vascular resistance, cardiac output) in patients with PAH; some beneficial effects on right ventricular hypertrophy also demonstrated in preclinical studies.1 6 20

• Does not interact with hepatic bile transport proteins (i.e., bile salt export pump [BSEP]) or organic anion-transporting polypeptides (OATP 1B1 and 1B3).1 6 9 10 15 18

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For macitentan, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to macitentan or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of macitentan in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of macitentan in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking macitentan, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using macitentan with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atazanavir
• Boceprevir
• Carbamazepine
• Clarithromycin
• Cobicistat
• Conivaptan
• Enzalutamide
• Fluconazole
• Fosphenytoin
• Idelalisib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Nefazodone
• Nelfinavir
• Phenytoin
• Posaconazole
• Primidone
• Rifabutin
• Rifampin
• Rifapentine
• Ritonavir
• Saquinavir
• St John's Wort
• Telaprevir
• Telithromycin
• Tipranavir
• Voriconazole

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of macitentan. Make sure you tell your doctor if you have any other medical problems, especially:

• Anemia (low red blood cells), severe or
• Fluid retention (edema) or
• Heart disease or
• Liver disease—Use with caution. May make these conditions worse.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

(ma si TEN tan)

• Opsumit

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetic changes were not considered clinically relevant. Canadian labeling does not recommend use in dialysis patients (has not been studied).

Oral: Swallow tablet whole. Do not split, crush, or chew tablets. May be administered with or without food.

Do not administer macitentan to a pregnant female patient because it may cause fetal harm. In female patients of reproductive potential, exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception.

For all female patients, macitentan is available only through a restricted program called the Opsumit Risk Evaluation and Mitigation Strategy (REMS).

Use is contraindicated in pregnant women. [US Boxed Warnings]: Macitentan may cause fetal harm if given to pregnant women; do not administer to women who are pregnant. Macitentan is available to females only through the restricted OPSUMIT Risk Evaluation and Mitigation Strategy (REMS) Program. All females of reproductive potential should have a negative pregnancy test prior to beginning therapy and testing should continue monthly during treatment and one month after discontinuing therapy. Females of childbearing potential should not become pregnant during therapy or for 1 month following discontinuation of macitentan by using acceptable methods of contraception. All females regardless of their reproductive potential must be enrolled in the REMS program; prescribers and pharmacies must also be enrolled in the program. Females of reproductive potential must be able to comply with pregnancy testing and contraception requirements of the program. Women may use one highly effective form of contraception (intrauterine device, contraceptive implant, or tubal sterilization) or a combination of methods (hormonal contraceptive with a barrier method or two barrier methods). A hormonal contraceptive or barrier method must be used in addition to a partner’s vasectomy, if that method is chosen. Females should be counseled on pregnancy prevention and planning and instructed to notify their prescriber immediately if a pregnancy should occur. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014). Fertility may be affected in males.

Applies to macitentan: oral tablet

Along with its needed effects, macitentan may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking macitentan:

• Decrease in the amount of urine
• noisy, rattling breathing
• pale skin
• swelling of the fingers, hands, feet, or lower legs
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• weight gain

• Abdominal or stomach pain or tenderness
• clay colored stools
• dark urine
• difficult, burning, or painful urination
• frequent urge to urinate
• lower back or side pain
• muscle aches and pains
• difficulty with breathing
• tightness in the chest
• yellow eyes or skin

Some side effects of macitentan may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Chills or fever
• cough
• sore throat
• stuffy or runny nose

No adjustment recommended.