macitentan (Rx)

Brand and Other Names:Opsumit
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 10mg

Pulmonary Arterial Hypertension

Indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization

10 mg PO qDay

Higher doses have not been studied and are not recommended

Dosage Modifications

Renal impairment

  • Severe (CrCl 15-29 mL/min): No dosage modification needed
  • Systemic exposure to macitentan and its active metabolite were increased by 30% and 60% respectively (not considered clinically relevant)

Hepatic impairment

  • Mild, moderate, or severe (Child-Pugh Class A, B, and C): No dosage modification needed
  • System exposure decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment respectively (not considered clinically relevant)

Dosing Considerations

Obtain pregnancy test in females of reproductive potential before initiating, monthly during treatment, and 1 month after discontinuing; initiate in females of reproductive potential only after a negative pregnancy test

Measure hemoglobin before initiating treatment and repeat during treatment as clinically indicated

Orphan Designations

Fixed dose combination of macitentan and tadalafil for treatment of pulmonary arterial hypertension

Fontan-palliated patients

Chronic thromboembolic pulmonary hypertension (CTEPH)

Orphan sponsor

  • Actelion Clinical Research, Inc; 1820 Chapel Avenue West, Suite 300; Cherry Hill, New Jersey 08002

Safety and efficacy not established

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Interactions

Interaction Checker

and macitentan

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Nasopharyngitis (20%)

            Headache (14%)

            Anemia (13%)

            Bronchitis (12%)

            1-10%

            Urinary tract infection (9%)

            Hemoglobin <10 g/dL (8.7%)

            Influenza (6%)

            Elevated aminotransferases >3 x ULN (3.4%)

            Elevated aminotransferases >8 x ULN (2.1%)

            Postmarketing Reports

            Immune system disorders: Hypersensitivity reactions (angioedema, pruritus and rash)

            Respiratory, thoracic and mediastinal disorders: Nasal congestion

            Gastrointestinal disorders: Elevations of liver aminotransferases (ALT, AST) and liver injury have been reported; in most cases alternative causes could be identified (heart failure, hepatic congestion, autoimmune hepatitis); ERAs have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure

            General disorders and administration site conditions: Edema/fluid retention; cases of edema and fluid retention occurred within weeks of starting macitentan, some requiring intervention with a diuretic, fluid management, or hospitalization for decompensated heart failure

            Cardiac disorders: Symptomatic hypotension

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            Warnings

            Black Box Warnings

            Pregnancy contraindication

            • Do not administer to pregnant women because it may cause fetal harm
            • Females of reproductive potential: Exclude pregnancy before starting 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 (see Pregnancy)

            Restricted distribution program

            • Because of risks of birth defects, available only through restricted distribution program called the Opsumit REMS program
            • May be dispensed only to patients enrolled in and meet all conditions of the REMS program
            • All females, regardless of reproductive potential, must enroll in the OPSUMIT REMS Program before initiating; male patients are not enrolled in the REMS
            • Females of reproductive potential must comply with the pregnancy testing and contraception requirements
            • Prescribers must be certified with the program by enrolling and completing training
            • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive macitentan

            Contraindications

            Pregnancy; consistently shown to have teratogenic effects in animal studies

            Cautions

            Other endothelin receptor antagonists (ERAs) have been associated with elevated liver aminotransferases, hepatotoxicity, and liver failure; obtain liver enzymes tests before initiating and repeat as clinically warranted; discontinue if aminotransferase elevations are accompanied by clinical symptoms of hepatoxicity

            ERAs associated with decreased hemoglobin and hematocrit concentrations; do not initiate if severe anemia present

            Monitor for signs of fluid retention after initiating therapy; if clinically significant fluid retention develops, evaluate patient to determine the cause, such as the therapy being administered or underlying heart failure, and the possible need to discontinue therapy

            If pulmonary edema occurs, consider the possibility of associated pulmonary veno-occlusive disease, and if confirmed, discontinue drug

            ERAs associated with adverse effects on spermatogenesis; counsel men about potential effects on fertility

            Drug interaction overview

            • Macitentan is a CYP3A4 substrate
            • Strong CYP3A4 inducers significantly reduce macitentan systemic exposure; avoid coadministration
            • Avoid coadministration with strong CYP3A4 inhibitors, as macitentan systemic exposure is ~doubled; use other PAH treat option when CYP3A4 inhibitors are needed as part of HIV treatment
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            Pregnancy & Lactation

            Pregnancy

            Based on data from animal reproduction studies, therapy may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy; there are risks to mother and fetus associated with pulmonary arterial hypertension in pregnancy; there are limited data on use in pregnant women; the drug was teratogenic in rabbits and rats at all doses tested; if drug is used during pregnancy, or if patient becomes pregnant while taking this drug, advise the patient of risk to a fetus

            In patients with pulmonary arterial hypertension, pregnancy is associated with increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor

            Pregnancy testing

            • Verify pregnancy status of females of reproductive potential prior to initiating therapy, monthly during treatment and one month after stopping treatment; the patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected; if pregnancy test is positive, the physician and patient must discuss risks to her, the pregnancy, and fetus

            Contraception

            • Female patients of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after stopping
            • 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

            Infertility

            • Based on findings in animals, drug may impair fertility in males of reproductive potential; not known whether effects on fertility would be reversible

            Lactation

            There are no data on presence of macitentan in human milk, effects on breastfed infant, or on milk production; because of potential for serious adverse reactions in breastfed infants advise women not to breastfeed during treatment

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Endothelin receptor antagonist (ERA); prevents binding of endothelin (ET)-1 to both ET-A and ET-B receptors with high affinity to ET receptors in pulmonary arterial smooth muscle cells; active metabolite 20% as potent as parent compound

            Absorption

            Peak plasma time: 8 hr

            Absolute bioavailability: Unknown

            Distribution

            Protein bound: >99%; mainly to albumin and to a lesser extent alpha-1-glycoprotein

            Vd: 50 L; 40 L (active metabolite)

            Metabolism

            Metabolized by liver: Mainly by CYP3A4, minor amount by CYP2C19; primarily metabolized by oxidative depropylation of the sulfamide to form active metabolite

            Active metabolite: At steady state, systemic exposure of active metabolite is 3-times the exposure of macitentan; active metabolite thought to contribute approximately 40% of total pharmacologic activity

            Elimination

            Half-life: 16 hr; 48 hr (active metabolite)

            Excretion: 50% urine; 24% feces

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            Administration

            Oral Administration

            May take with or without food

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.