Macitentan

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Opsumit: 10 mg [contains soybean lecithin]

Pharmacology

Mechanism of Action

Blocks endothelin (ET)-1 from binding to endothelin receptor subtypes ET_A and ET_B on vascular endothelium and smooth muscle. Stimulation of these receptors is associated with vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation.

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss: 50 L (active metabolite: 40 L)

Metabolism

Hepatic via CYP3A4 (major) and CYP2C19 to its active metabolite

Excretion

Urine (~50%); feces (~24%)

Time to Peak

Plasma: 8 hours

Half-Life Elimination

~16 hours (active metabolite: ~48 hours)

Protein Binding

>99% primarily to albumin

Use: Labeled Indications

Pulmonary arterial hypertension: Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to reduce risks of disease progression and hospitalization

Contraindications

Pregnancy

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to macitentan or any component of the formulation; breastfeeding.

Dosage and Administration

Dosing: Adult

Pulmonary arterial hypertension: Oral: 10 mg once daily; maximum 10 mg daily

Dosing: Geriatric

Refer to adult dosing.

Administration

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

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Macitentan. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Macitentan. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Headache (14%)

Hematologic & oncologic: Anemia (13%)

Respiratory: Nasopharyngitis (≤20%), pharyngitis (≤20%), bronchitis (12%)

1% to 10%:

Genitourinary: Urinary tract infection (9%)

Hematologic & oncologic: Decreased hemoglobin (9%)

Hepatic: Increased liver enzymes (>8 x ULN: 2%)

Infection: Influenza (6%)

<1%, postmarketing, and/or case reports: Angioedema, edema, fluid retention, hepatic insufficiency, hepatotoxicity, hypersensitivity reaction, increased serum ALT, increased serum AST, nasal congestion, pruritus, rash, symptomatic hypotension

Warnings/Precautions

Concerns related to adverse effects:

• Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization) associated with other endothelin antagonists. Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with severe chronic heart failure.
• Hematologic effects: A reduction in hematocrit/hemoglobin has been observed and may occur early in therapy with subsequent stabilization. Decreases in hemoglobin rarely required transfusion. Measure hemoglobin prior to initiating therapy and repeat as clinically appropriate. Use is not recommended in patients with severe anemia.
• Hepatic effects: Increases in serum liver aminotransferases, hepatotoxicity, and liver failure have been reported. Monitor transaminases prior to initiation of therapy and repeat as clinically appropriate. Discontinue treatment in patients who develop elevated transaminases either in combination with symptoms of hepatic injury (eg, anorexia, dark urine, fatigue, fever, itching, jaundice, nausea, right upper quadrant pain, vomiting) or elevated bilirubin (>2 x the upper limit of normal [ULN]). Upon normalization of hepatic enzymes, may consider reinitiation of therapy in patients not experiencing clinical signs of hepatotoxicity.
• Spermatogenesis: Sperm count may be reduced in men during treatment. Advise male patients of potential effects on fertility.

Disease-related concerns:

• Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the possibility of PVOD; discontinue if PVOD is confirmed.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Macitentan may cause fetal harm if given to pregnant women; do not administer to women who are pregnant. 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. 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.
• REMS program: [US Boxed Warning]: Macitentan is available to females only through the restricted OPSUMIT Risk Evaluation and Mitigation Strategy (REMS) Program. 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. Call 1-866-228-3546 or visit http://www.opsumitrems.com for more information.

Monitoring Parameters

Monitor for significant peripheral edema and evaluate etiology if it occurs; measure liver enzymes prior to initiation and repeat as clinically appropriate (Canadian labeling recommends monthly monitoring of liver enzymes during the first year of therapy and then as clinically appropriate); monitor for clinical signs and symptoms of liver injury (eg, abdominal pain, anorexia, dark urine, fatigue, fever, itching, jaundice, nausea, vomiting); hemoglobin and hematocrit prior to initiation and repeat as clinically appropriate (Canadian labeling recommends to repeat hemoglobin after first month of therapy and then as clinically appropriate).

A woman of childbearing potential must have a negative pregnancy test prior to the initiation of therapy, monthly during treatment, and 1 month after stopping treatment.

Pregnancy

Pregnancy Considerations

[US Boxed Warnings]: Do not administer macitentan to a pregnant female because it may cause fetal harm. Based on data from animal reproduction studies, macitentan may cause harm if administered during pregnancy; therefore, use is contraindicated in pregnant women. Untreated maternal pulmonary arterial hypertension is also associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (ESC [Regitz-Zagrosek 2018]; McLaughlin 2009; Taichman 2014).

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

[US Boxed Warnings]: 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. 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.

Patient Education

What is this drug used for?

• It is used to treat high blood pressure in the lungs.

Frequently reported side effects of this drug

• Headache
• Stuffy nose
• Sore throat
• Bronchitis
• Flu-like symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• Severe loss of strength and energy
• Trouble breathing
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Cough
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.