Opsumit

Endothelin Receptor Antagonists for PAH

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.
Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

May be taken with or without food.

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

edema / Delayed / 21.9-21.9
anemia / Delayed / 13.0-13.0
elevated hepatic enzymes / Delayed / 2.1-3.4
infertility / Delayed / Incidence not known
fluid retention / Delayed / Incidence not known
hypotension / Rapid / Incidence not known

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

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 in both rabbits and rats, as well as reduced pup survival and impairment in male fertility of the offspring. 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. To prevent macitentan exposure during pregnancy, a REMS program has been developed. This program requires prescribers, pharmacists, and patients to comply with certain conditions before prescribing, dispensing, or receiving macitentan. 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]

Opsumit

Rx

Oral endothelin receptor antagonist
Used for the treatment of pulmonary arterial hypertension
May cause embryo-fetal toxicity and fetal death; female patients may only receive macitentan through the Opsumit REMS Program

10 mg PO once daily.

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

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

Adagrasib: (Major) Avoid coadministration of macitentan with adagrasib due to the risk of increased macitentan exposure and adverse effects. Consider alternative treatment options for pulmonary hypertension if treatment with adagrasib is necessary. Macitentan is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased macitentan exposure by approximately 2-fold.
Amiodarone: (Major) Avoid coadministration of macitentan with amiodarone due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and amiodarone is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
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.
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.
Brodalumab: (Major) Avoid coadministration of macitentan with brodalumab due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and brodalumab is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
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.
Ceritinib: (Major) Avoid coadministration of macitentan with ceritinib due to the risk of increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor approximately doubled macitentan exposure.
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: (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.
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.
Elvitegravir; 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.
Elvitegravir; Cobicistat; 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.
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.
Fluconazole: (Major) Avoid coadministration of macitentan with fluconazole due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and fluconazole is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
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 coadministration of macitentan with ketoconazole due to the risk of increased macitentan exposure and adverse effects. Consider alternative treatment options for pulmonary hypertension if treatment with ketoconazole is necessary. Macitentan is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased macitentan exposure by approximately 2-fold.
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.
Levoketoconazole: (Major) Avoid coadministration of macitentan with ketoconazole due to the risk of increased macitentan exposure and adverse effects. Consider alternative treatment options for pulmonary hypertension if treatment with ketoconazole is necessary. Macitentan is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased macitentan exposure by approximately 2-fold.
Lonafarnib: (Major) Avoid coadministration of macitentan with lonafarnib due to the risk of increased macitentan exposure and adverse effects. Consider alternative treatment options for pulmonary hypertension if treatment with lonafarnib is necessary. Macitentan is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2-fold.
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.
Nirmatrelvir; 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.
Rifapentine: (Major) Avoid coadministration of macitentan with rifapentine due to the risk of decreased macitentan exposure which may lead to reduced efficacy. Macitentan is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
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.
Secukinumab: (Major) Avoid coadministration of macitentan with secukinumab due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and secukinumab is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
Sparsentan: (Contraindicated) Concomitant use of sparsentan and endothelin receptor antagonists (ERAs) is contraindicated due to the additive risk for serious adverse effects such as hypotension, syncope, hyperkalemia, and renal dysfunction.
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.
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.
Tucatinib: (Major) Avoid coadministration of macitentan with tucatinib due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
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.

Opsumit Oral Tab: 10mg

10 mg/day PO.

10 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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]

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. In healthy patients, the apparent 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 to 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, CYP2C9
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. According to the manufacturer, coadministration with a moderate dual or combined inhibitors of CYP3A4 and CYP2C9 are predicted to result in a 4-fold increase in macitentan exposure.[56260]

Peak plasma concentration occurs approximately 8 hours after oral administration. Absolute bioavailability is unknown. Based on a study in healthy individuals, exposure to macitentan and its active metabolite are unchanged after a high-fat meal; therefore, macitentan may be administered with or without food.[56260]

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 in both rabbits and rats, as well as reduced pup survival and impairment in male fertility of the offspring. 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. To prevent macitentan exposure during pregnancy, a REMS program has been developed. This program requires prescribers, pharmacists, and patients to comply with certain conditions before prescribing, dispensing, or receiving macitentan. 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]

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