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  • CLASSES

    Endothelin Receptor Antagonists
    Pulmonary Hypertension Agents

    BOXED WARNING

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Macitentan may be associated with reproductive risk. Verify the pregnancy status of females of childbearing potential with pregnancy testing prior to starting macitentan, monthly during treatment, and for 1 month after treatment discontinuation. Advise the patient to contact her healthcare provider immediately for pregnancy testing if menses is delayed or pregnancy is suspected. If a pregnancy test is positive, discuss the risks to her, the pregnancy, and the fetus. Discuss contraception requirements with the patient. Females of childbearing potential must use acceptable methods of contraception during treatment and for 1 month after discontinuation. The patient may choose 1 highly effective contraceptive method, including an intrauterine device (IUD), contraceptive implant, or tubal sterilization, or a combination of methods (e.g., hormonal contraceptive with a barrier method or 2 barrier methods). If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Counsel patients on pregnancy planning and prevention, including emergency contraception. Additionally, like other endothelin receptor antagonists, macitentan may have an adverse effect on spermatogenesis. Based on animal findings, macitentan may cause infertility in males of reproductive potential. It is not known whether the effects on fertility would be reversible. Counsel men about potential effects on fertility.[56260]

    DEA CLASS

    Rx

    DESCRIPTION

    Oral endothelin receptor antagonist
    Used for the treatment of pulmonary arterial hypertension
    May cause embryo-fetal toxicity including birth defects and fetal death; female patients may only receive macitentan through a restricted program

    COMMON BRAND NAMES

    Opsumit

    HOW SUPPLIED

    Opsumit Oral Tab: 10mg

    DOSAGE & INDICATIONS

    For the treatment of pulmonary hypertension (PAH, WHO Group 1) to delay disease progression.
    Oral dosage
    Adults

    10 mg PO once daily.

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO.

    Geriatric

    10 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Because of the risk of birth defects, macitentan is available to female patients only through a special restricted distribution program called the Opsumit REMS Program.

    Oral Administration

    May be taken with or without food.

    Oral Solid Formulations

    Do not be split, crush, or chew tablets.

    STORAGE

    Opsumit:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatic disease

    Endothelin receptor antagonists (ERAs) have caused elevated hepatic enzymes, hepatotoxicity, and hepatic failure. Obtain liver function tests prior to initiation of macitentan and repeat during treatment as clinically indicated. Advise patients to report symptoms suggestive of hepatic disease (e.g., nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, itching). Discontinue macitentan if clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin more than 2 times the upper limit of normal (ULN) or clinical symptoms of hepatotoxicity. Consider reinitiation when hepatic enzyme concentrations normalize in patients who have not experienced clinical symptoms of hepatotoxicity.[56260]

    Anemia

    Do not initiate macitentan in patients with severe anemia. Monitor hemoglobin prior to treatment initiation and repeat as clinically indicated. Decreases in hemoglobin and hematocrit concentrations have occurred with macitentan treatment; such decreases occurred early and stabilized thereafter.[56260]

    Pulmonary edema, veno-occlusive disease (VOD)

    Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (VOD). Consider the possibility of pulmonary VOD in patients who develop pulmonary edema. Discontinue use of macitentan if pulmonary VOD is confirmed.[56260]

    Pregnancy

    Macitentan may cause fetal harm (e.g., birth defects, fetal death) when administered during pregnancy and is contraindicated in females who are pregnant. There are limited data on macitentan use in pregnant women. Macitentan was teratogenic in rabbits and rats at all doses tested. Administration resulted in cardiovascular and mandibular arch fusion abnormalities, as well as reduced pup survival. In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction, and premature labor. If macitentan is used during pregnancy or if the patient becomes pregnant while taking macitentan, advise the patient of the potential risk to a fetus.[56260]

    Breast-feeding

    There are no data on the presence of macitentan in human milk, the effects on the breast-fed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breast-fed infants from macitentan, advise women against breast-feeding during treatment with macitentan.[56260] Epoprostenol may be a reasonable alternative in breast-feeding women.[49831]

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Macitentan may be associated with reproductive risk. Verify the pregnancy status of females of childbearing potential with pregnancy testing prior to starting macitentan, monthly during treatment, and for 1 month after treatment discontinuation. Advise the patient to contact her healthcare provider immediately for pregnancy testing if menses is delayed or pregnancy is suspected. If a pregnancy test is positive, discuss the risks to her, the pregnancy, and the fetus. Discuss contraception requirements with the patient. Females of childbearing potential must use acceptable methods of contraception during treatment and for 1 month after discontinuation. The patient may choose 1 highly effective contraceptive method, including an intrauterine device (IUD), contraceptive implant, or tubal sterilization, or a combination of methods (e.g., hormonal contraceptive with a barrier method or 2 barrier methods). If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Counsel patients on pregnancy planning and prevention, including emergency contraception. Additionally, like other endothelin receptor antagonists, macitentan may have an adverse effect on spermatogenesis. Based on animal findings, macitentan may cause infertility in males of reproductive potential. It is not known whether the effects on fertility would be reversible. Counsel men about potential effects on fertility.[56260]

    ADVERSE REACTIONS

    Severe

    teratogenesis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    anemia / Delayed / 13.0-13.0
    elevated hepatic enzymes / Delayed / 2.1-3.4
    infertility / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    pharyngitis / Delayed / 20.0-20.0
    headache / Early / 14.0-14.0
    infection / Delayed / 9.0-9.0
    influenza / Delayed / 6.0-6.0
    oligospermia / Delayed / Incidence not known
    nasal congestion / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Apalutamide: (Major) Avoid coadministration of macitentan with apalutamide due to decreased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced systemic availability of the pharmacologically active moieties of macitentan by approximately 50% or more, which may lead to reduced efficacy.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if macitentan and aprepitant, fosaprepitant are used concurrently and monitor for an increase in macitentan-related adverse effects for several days after administration of a multi-day aprepitant regimen. Macitentan is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of macitentan. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Boceprevir: (Major) Avoid concurrent use of macitentan and boceprevir. Boceprevir is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with boceprevir is necessary.
    Brigatinib: (Moderate) Monitor for decreased efficacy of macitentan if coadministration with brigatinib is necessary. Macitentan is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of macitentan may decrease.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Cobicistat: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Darunavir; Cobicistat: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concurrent use of macitentan and ritonavir. Ritonavir is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor approximately doubled macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ritonavir is necessary.
    Delavirdine: (Major) Avoid concurrent use of macitentan and delavirdine. Delavirdine is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with delavirdine is necessary.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
    Elbasvir; Grazoprevir: (Moderate) Administering macitentan with elbasvir; grazoprevir may result in elevated macitentan plasma concentrations. Macitentan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enzalutamide: (Major) Avoid coadministration of macitentan with enzalutamide due to decreased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced systemic availability of the pharmacologically active moieties of macitentan by approximately 50% or more, which may lead to reduced efficacy.
    Indinavir: (Major) Avoid concurrent use of macitentan and indinavir. Indinavir is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with indinavir is necessary.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with macitentan may result in increased serum concentrations of macitentan. Macitentan is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of macitentan and rifampin. Rifampin is a strong inducer of CYP3A4 and significantly reduces macitentan exposure.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of macitentan and rifampin. Rifampin is a strong inducer of CYP3A4 and significantly reduces macitentan exposure.
    Itraconazole: (Major) Avoid concurrent use of macitentan and itraconazole. Itraconazole is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with itraconazole is necessary.
    Ketoconazole: (Major) Avoid concurrent use of macitentan and ketoconazole. Ketoconazole is a strong inhibitor of CYP3A4. Coadminsitration with macitentan approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ketoconazole is necessary.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of macitentan; monitor for potential reduction in efficacy. Macitentan is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of macitentan; monitor for potential reduction in efficacy. Macitentan is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) An increase in the plasma concentration of macitentan may occur if given with letermovir. Avoid coadministration in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If treatment with letermovir and cyclosporine must be continued, consider use of an alternative pulmonary artery hypertension medication. Macitentan is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with a strong CYP3A4 inhibitor resulted in a doubling of macitentan exposure.
    Lopinavir; Ritonavir: (Major) Avoid concurrent use of macitentan and ritonavir. Ritonavir is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor approximately doubled macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ritonavir is necessary.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of macitentan by significantly decreasing its systemic exposure; avoid concomitant use. Macitentan is primarily metabolized via CYP3A4, with a minor contribution from CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce CYP2C19.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Nefazodone: (Major) Avoid concurrent use of macitentan and nefazodone. Nefazodone is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with nefazodone is necessary.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concurrent use of macitentan and ritonavir. Ritonavir is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor approximately doubled macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ritonavir is necessary.
    Ribociclib: (Major) Avoid coadministration of macitentan with ribociclib due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Ribociclib; Letrozole: (Major) Avoid coadministration of macitentan with ribociclib due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Rifampin: (Major) Avoid coadministration of macitentan and rifampin. Rifampin is a strong inducer of CYP3A4 and significantly reduces macitentan exposure.
    Ritonavir: (Major) Avoid concurrent use of macitentan and ritonavir. Ritonavir is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor approximately doubled macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ritonavir is necessary.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of macitentan and St. John's Wort, Hypericum perforatum. St. John's Wort is a strong inducer of CYP3A4. Coadministration with macitentan significantly reduces macitentan exposure.
    Sympathomimetics: (Major) Avoid use of sympathomimetic agents with macitentan. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including macitentan. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Telaprevir: (Major) Avoid concurrent use of macitentan and telaprevir. Telaprevir is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with telaprevir is necessary.
    Telithromycin: (Major) Avoid concurrent use of macitentan and telithromycin. Telithromycin is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with telithromycin is necessary.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and macitentan is necessary, as the systemic exposure of macitentan may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of macitentan; consider increasing the dose of macitentan if necessary. Macitentan is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tipranavir: (Major) Avoid concurrent use of macitentan and tipranavir. Tipranavir is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with tipranavir is necessary.
    Voriconazole: (Major) Avoid coadministration of macitentan with voriconazole due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and voriconanzole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.

    PREGNANCY AND LACTATION

    Pregnancy

    Macitentan may cause fetal harm (e.g., birth defects, fetal death) when administered during pregnancy and is contraindicated in females who are pregnant. There are limited data on macitentan use in pregnant women. Macitentan was teratogenic in rabbits and rats at all doses tested. Administration resulted in cardiovascular and mandibular arch fusion abnormalities, as well as reduced pup survival. In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction, and premature labor. If macitentan is used during pregnancy or if the patient becomes pregnant while taking macitentan, advise the patient of the potential risk to a fetus.[56260]

    Macitentan may be associated with reproductive risk. Verify the pregnancy status of females of childbearing potential with pregnancy testing prior to starting macitentan, monthly during treatment, and for 1 month after treatment discontinuation. Advise the patient to contact her healthcare provider immediately for pregnancy testing if menses is delayed or pregnancy is suspected. If a pregnancy test is positive, discuss the risks to her, the pregnancy, and the fetus. Discuss contraception requirements with the patient. Females of childbearing potential must use acceptable methods of contraception during treatment and for 1 month after discontinuation. The patient may choose 1 highly effective contraceptive method, including an intrauterine device (IUD), contraceptive implant, or tubal sterilization, or a combination of methods (e.g., hormonal contraceptive with a barrier method or 2 barrier methods). If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Counsel patients on pregnancy planning and prevention, including emergency contraception. Additionally, like other endothelin receptor antagonists, macitentan may have an adverse effect on spermatogenesis. Based on animal findings, macitentan may cause infertility in males of reproductive potential. It is not known whether the effects on fertility would be reversible. Counsel men about potential effects on fertility.[56260]

    MECHANISM OF ACTION

    Macitentan is a dual endothelin (ET) receptor antagonist. In patients with pulmonary arterial hypertension, plasma ET-1 concentrations are elevated and involved in the production of vasoconstriction, fibrosis, proliferation, vascular hypertrophy, inflammation, and organ damage. Macitentan prevents the binding of ET-1 to ETA and ETB receptors on human pulmonary arterial smooth muscle cells and does so with high affinity and prolonged occupancy. The active metabolite of macitentan is estimated to be approximately 20% as potent in antagonizing the ET receptors as macitentan in vitro.[56260]

    PHARMACOKINETICS

    Macitentan is administered orally. Macitentan and its active metabolite are highly bound to plasma proteins (more than 99%), mainly albumin and, to a lesser extent, alpha-1-acid glycoprotein. The volume of distribution of macitentan and its active metabolite are 50 L and 40 L, respectively. Macitentan is metabolized primarily by CYP3A4, with minor contributions by CYP2C8, CYP2C9, and CYP2C19. In patients with pulmonary arterial hypertension, the systemic exposure of the active metabolite is 3-times the exposure of macitentan and contributes about 40% of the total pharmacologic activity. Approximately 50% of radioactive drug is eliminated via urine and 24% is recovered from feces. The apparent half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively.[56260]
     
    The hemodynamic parameters of macitentan were assessed in a placebo-controlled trial. After 6 months of treatment with macitentan 10 mg daily, patients (n = 57) achieved a median reduction in pulmonary vascular resistance of 37% (95% CI, 22 to 49) and an increase in cardiac index of 0.6 L/minute/m2 (95% CI, 0.3 to 0.9) compared to placebo (n = 67).[56260]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
    Macitentan is metabolized primarily by CYP3A4, with minor contributions by CYP2C8, CYP2C9, and CYP2C19. Strong CYP3A4 inhibitors and inducers are likely to result in alteration of macitentan exposure at steady state.[56260]

    Oral Route

    Peak plasma concentration occurs approximately 8 hours after oral administration. Absolute bioavailability is unknown. Exposure is unchanged after a high-fat meal; therefore, macitentan may be administered with or without food.[56260]