Macitentan
Indications
Macitentan is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO functional class (FC) II to III. Also, efficacy has been shown in a:
- PAH population including idiopathic and heritable PAH
- PAH associated with connective tissue disorders, and
- PAH associated with congenital heart disease.
Pharmacology
Endothelin (ET)-1 and its receptors (ETA and ETB ) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro. The clinical impact of dual endothelin blockage is unknown.
Dosage & Administration
The recommended dosage of Macitentan is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended. Macitentan tablets are to be swallowed whole with water, may be taken with or without food. Macitentan tablet should be taken every day at about the same time. If a dose has been missed, the patient should be taken it as soon as possible and then take the next dose at the regularly scheduled time. Two doses should not be taken at the same time, including the missed dose.
Elderly: There is limited clinical data with Macitentan in patients over the age of 75 years, therefore Macitentan should be used with caution in this population.
Pediatric population: The safety of Macitentan in children and adolescents below 18 years has not yet been established.
Elderly: There is limited clinical data with Macitentan in patients over the age of 75 years, therefore Macitentan should be used with caution in this population.
Pediatric population: The safety of Macitentan in children and adolescents below 18 years has not yet been established.
Interaction
Strong CYP3A4 Inducers: Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of Macitentan with strong CYP3A4 inducers should be avoided.
Strong CYP3A4 Inhibitors: Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of Macitentan with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment
Strong CYP3A4 Inhibitors: Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of Macitentan with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment
Contraindications
Hypersensitivity to the active component of the product, pregnancy, breastfeeding, patients with severe hepatic impairment.
Side Effects
The most commonly reported adverse reactions are nasopharyngitis (14%), headache (13.6%) and anemia (13.2%).
Pregnancy & Lactation
Macitentan treatment should only be initiated in women of childbearing potential when the absence of pregnancy has been verified. Women should not become pregnant for 1 month after discontinuation of Macitentan. Monthly pregnancy tests during treatment with Macitentan are recommended to allow the early detection of pregnancy. It is unknown whether Macitentan is excreted in human milk. Macitentan is contraindicated during breastfeeding.
Male fertility: The development of testicular tubular atrophy in male animals was observed after treatment with Macitentan The relevance of this finding to humans is unknown, but a deterioration of spermatogenesis could happen.
Male fertility: The development of testicular tubular atrophy in male animals was observed after treatment with Macitentan The relevance of this finding to humans is unknown, but a deterioration of spermatogenesis could happen.
Precautions & Warnings
The benefit/risk balance of Macitentan has not been established in patients with WHO class I functional status of pulmonary arterial hypertension.
Hepatic impairment: Elevations of liver aminotransferases (AST, ALT) have been associated with PAH and with endothelin receptor antagonists (ERAs). Macitentan is not to be initiated in patients with severe hepatic impairment or elevated aminotransferases (>3 × ULN). Liver enzyme test should be obtained prior to initiation of Macitentan.
Hemoglobin concentration: Decrease in hemoglobin concentrations has been associated with endothelin receptor antagonists (ERAs) including Macitentan. But Macitentan-related decreases in hemoglobin concentration were not progressive. Stabilized after the first 4-12 weeks of treatment Initiation of Macitentan is not recommended in patients with severe anemia.
Pulmonary veno-occlusive disease: Consequently, if signs of pulmonary oedema occur when Macitentan is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered.
Concomitant use with strong CYP3A4 inducers: In the presence of strong CYP3A4 inducers reduced efficacy of Macitentan could occur. The combination of Macitentan with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort, carbamazepine, and phenytoin) should be avoided.
Concomitant use with strong CYP3A4 inhibitors: Caution should be taken when Macitentan is administered concomitantly with strong or moderate CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir).
Concomitant use with moderate dual CYP3A4 and CYP2C9 inhibitors: Caution should be taken when Macitentan is administered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (e.g., fluconazole and amiodarone)
Caution should also be exercised when Macitentan is administered concomitantly with botha moderate CYP3A4 inhibitor (e.g. ciprofloxacin, cyclosporine, dilitiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitor.
Renal impairment: Based on PK data no dose adjustment is required in patient with renal impairment. There is no clinical data with the use of Macitentan in PAH patients with severe renal impairment or patients undergoing dialysis. Caution is recommended in this population.
Hepatic impairment: Elevations of liver aminotransferases (AST, ALT) have been associated with PAH and with endothelin receptor antagonists (ERAs). Macitentan is not to be initiated in patients with severe hepatic impairment or elevated aminotransferases (>3 × ULN). Liver enzyme test should be obtained prior to initiation of Macitentan.
Hemoglobin concentration: Decrease in hemoglobin concentrations has been associated with endothelin receptor antagonists (ERAs) including Macitentan. But Macitentan-related decreases in hemoglobin concentration were not progressive. Stabilized after the first 4-12 weeks of treatment Initiation of Macitentan is not recommended in patients with severe anemia.
Pulmonary veno-occlusive disease: Consequently, if signs of pulmonary oedema occur when Macitentan is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered.
Concomitant use with strong CYP3A4 inducers: In the presence of strong CYP3A4 inducers reduced efficacy of Macitentan could occur. The combination of Macitentan with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort, carbamazepine, and phenytoin) should be avoided.
Concomitant use with strong CYP3A4 inhibitors: Caution should be taken when Macitentan is administered concomitantly with strong or moderate CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir).
Concomitant use with moderate dual CYP3A4 and CYP2C9 inhibitors: Caution should be taken when Macitentan is administered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (e.g., fluconazole and amiodarone)
Caution should also be exercised when Macitentan is administered concomitantly with botha moderate CYP3A4 inhibitor (e.g. ciprofloxacin, cyclosporine, dilitiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitor.
Renal impairment: Based on PK data no dose adjustment is required in patient with renal impairment. There is no clinical data with the use of Macitentan in PAH patients with severe renal impairment or patients undergoing dialysis. Caution is recommended in this population.
Overdose Effects
Macitentan has been administered as a single dose of up to 600 mg to healthy subjects. Adverse reactions of headache, nausea, and vomiting were observed. In the event of an overdose, standard supportive measures must be taken, as required. Due to the high degree of protein binding of Macitentan, dialysis is unlikely to be effective.
Therapeutic Class
Anti-hypertensive
Storage Conditions
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
