Macitentan

Macitentan is an Endothelin receptor antagonist belonging to antihypertensive agent.

Macitentan is an endothelin receptor antagonist used to manage pulmonary arterial hypertension to delay disease progression.

The maximum plasma concentration of Macitentan is achieved about 8 hours after oral administration. Macitentan may therefore be taken with or without food. Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of Macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects. Following oral administration, the apparent elimination half-lives of Macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. About 24% of the radioactive drug material was recovered from feces.

Macitentan shows common side effects like Stuffy nose, sore throat, Cough, flu like symptoms, Headache, urgent, frequent, or painful urination, rash.

Macitentan is available in the form of an Oral Tablet.

Macitentan is available in India, US, South Africa, New Zealand, Canada, Japan, China, and Australia.

Macitentan belongs to the antihypertensive agent acts as an Endothelin receptor antagonist.

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

The Data of onset and duration of action of Macitentan is not clinically established.

The Tmax of Macitentan is approximately 8 hours.

Macitentan is available in the form of Oral Tablet.

Macitentan tablets is taken orally, usually once daily.

Macitentan is used for the treatment of pulmonary arterial hypertension (PAH) (WHO class 1), a condition characterized by high blood pressure in the vessels carrying blood from the heart to the lungs. It is used alone or in combination with other medicines to treat PAH and improve exercise tolerance.

Macitentan is an Endothelin receptor antagonist belonging to antihypertensive agent.

Macitentan inhibits the binding of endothelin (ET)-1 from binding to both type A (ET_A) and type B (ET_B) receptors. ET-1 is a potent vasoconstrictor which plays a pathogenic role in pulmonary arterial hypertension (PAH). Blockade of ET-1 leads to vasodilatation, inhibition of smooth muscle proliferation and improved exercise capacity.

Macitentan is approved for use in the following clinical indications

• Pulmonary Arterial Hypertension

Macitentan is an Endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.

• Pulmonary Arterial Hypertension

Oral: 10 mg once daily; maximum 10 mg/day.

Macitentan is available in various strengths as 10mg.

Macitentan is available in the form of Oral Tablet.

• Dosage Adjustment in Kidney Patient

There are no dosage adjustments provided.

• Dosage Adjustment in Hepatic impairment Patient

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.

Macitentan is contraindicated in patients with

• Pregnancy

Macitentan may cause fetal harm when administered to a pregnant woman. Macitentan is contraindicated in females who are pregnant. Macitentan was consistently shown to have teratogenic effects when administered to animals. If Macitentan is used during pregnancy, advise the patient of the potential risk to a fetus.

• Hypersensitivity

Macitentan is contraindicated in patients with a history of a hypersensitivity reaction to Macitentan or any component of the product.

• Fluid retention/peripheral edema

Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have been post marketing 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.

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 not to breastfeed during treatment with Macitentan.

Based on data from animal reproduction studies, Macitentan may cause harm if administered during pregnancy; therefore, use is contraindicated in pregnant women. Untreated maternal pulmonary arterial hypertension is also associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy.

Common Adverse effects

• Anemia, Headache, Bronchitis, nasopharyngitis, pharyngitis, Urinary tract infection, Increased serum transaminases, Influenza.

Rare Adverse effects

• Edema, symptomatic hypotension, Fluid retention, Hepatic injury (including fulminant hepatitis, hepatic failure), Angioedema, hypersensitivity reaction, Nasal congestion.

• 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.

• Moderate Dual or Combined CYP3A4 And CYP2C9 Inhibitors

Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase Macitentan exposure approximately 4-fold based on physiologically based pharmacokinetic (PBPK) modelling. Avoid concomitant use of Macitentan with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone). Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with Macitentan should also be avoided.

The common side effects of Macitentan include the following

• Common
  

Stuffy nose, sore throat, Cough, flu like symptoms, Headache, urgent, frequent, or painful urination, rash.

• Rare

Itchy skin, dark urine, yellowing of your skin or eyes, pain in the upper right part of your stomach, unexplained nausea or vomiting, loss of appetite, extreme tiredness, fever, swelling of the face, throat, tongue, lips, and eyes, difficulty swallowing or breathing, hoarseness, shortness of breath, especially when lying down, coughing up pink, frothy sputum or blood, unusual weight increase, swelling of the ankles or legs.

• Pregnancy

Pregnancy Category

Based on data from animal reproduction studies, Macitentan 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 the mother and the fetus associated with pulmonary arterial hypertension in pregnancy (see Clinical Considerations). There are limited data on Macitentan use in pregnant women. Macitentan was teratogenic in rabbits and rats at all doses tested. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

• Nursing Mothers

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 not to breastfeed during treatment with Macitentan.

• Pediatric Use

The safety and efficacy of Macitentan in children have not been established.

• Geriatric Use

Of the total number of subjects in the clinical study of Macitentan for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Macitentan has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed. In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because Macitentan is highly protein-bound.

Pharmacodynamic

Macitentan acts primarily by reducing vasoconstriction and cell proliferation due to endothelin overexpression.

Pharmacokinetics

• Absorption

The maximum plasma concentration of Macitentan is achieved about 8 hours after oral administration. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to Macitentan and its active metabolite were unchanged after a high fat breakfast. Macitentan may therefore be taken with or without food.

• Distribution

Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of Macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects.

• Metabolism and Excretion

Following oral administration, the apparent elimination half-lives of Macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with minor contributions of CYP2C8, CYP2C9, and CYP2C19. At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to Macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled Macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces.

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