Skip to Content

Macitentan

Pronunciation

(ma si TEN tan)

Index Terms

  • ACT-064992

Dosage Forms

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

Tablet, Oral:

Opsumit: 10 mg [contains soybean lecithin]

Brand Names: U.S.

  • Opsumit

Pharmacologic Category

  • Endothelin Receptor Antagonist
  • Vasodilator

Pharmacology

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

Distribution

Vss: 50 L (active metabolite: 40 L)

Metabolism

Hepatic via CYP3A4 (major) and CYP2C19; Formation of active metabolite via oxidative depropylation of the sulfamide

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 delay disease progression.

Contraindications

Pregnancy

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

Dosing: Adult

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

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).

Dosing: Hepatic Impairment

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetic changes were not considered clinically relevant.

Canadian labeling:

Baseline ALT or AST >3x ULN: Initiation of therapy is not recommended.

Mild impairment: Dosage adjustment not necessary.

Moderate to severe impairment: Use is not recommended.

Administration

Oral: Swallow tablet whole. Do not split, crush, or chew tablets. May be administered with or without food. Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

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. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

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

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

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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. 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 (<10 g/dL: 9%)

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

Infection: Influenza (6%)

<1% (Limited to important or life-threatening): Fluid retention, hypersensitivity reaction, nasal congestion, symptomatic hypotension

ALERT: U.S. Boxed Warning

Pregnancy:

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.

REMS program:

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

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. No changes in sperm function or hormone levels have been noted in animal studies. 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

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 Risk Factor

X

Pregnancy Considerations

Adverse events were observed in animal reproduction studies; 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 (Badesch, 2007; McLaughlin, 2009). Fertility may be affected in males.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, rhinitis, pharyngitis, or flu-like symptoms. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), loss of strength and energy, shortness of breath, excessive weight gain, swelling of arms or legs, bruising, bleeding, dysuria, or difficult urination (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Hide