Macitentan (Opsumit) is an oral endothelin receptor inhibitor. It is used in patients with pulmonary arterial hypertension as it causes vasodilation and has anti-inflammatory and antifibrotic properties.

Macitentan (Opsumit) Uses:

• Pulmonary arterial hypertension:

  • To lower the risks of hospitalisation and illness progression, it is recommended for the treatment of WHO group 1 pulmonary arterial hypertension.

Macitentan (Opsumit) Dose in Adults:

Macitentan (Opsumit) Dose in the treatment of pulmonary arterial hypertension:

• One daily oral dose of 10 mg.
• The daily dosing cap is 10 mg.

Macitentan (Opsumit) Use in Children:

Not indicated.

Macitentan (Opsumit) Pregnancy Risk Category: X

• [US Boxed Warnings]:

• Avoid using macitentan in pregnant females as it may cause fetal harm.
  • Animal reproduction studies have found adverse fetal outcomes when it was administered during pregnancy.
  • Therefore, its use in pregnancy is contraindicated.
  • Women with moderate to severe pulmonary arterial hypertension are usually advised to avoid pregnancy as pulmonary hypertension has also been associated with an increase in mortality and morbidity including intrauterine growth retardation, spontaneous abortion, and premature labor.

• [US Boxed Warnings]:

• Only the Opsumit Risk Evaluation and Mitigation Strategy, a limited initiative, makes macitentan available to all female patients (REMS).
  • Regardless of whether they are capable of having children, all female patients must be registered in the REMS programme.
  • The scheme also requires the enrollment of pharmacies and prescribers.
  • Females with reproductive potential who are provided the medication must be able to adhere to the program's guidelines for pregnancy testing and contraception.

• [US Boxed Warnings]:

• In order to rule out pregnancy in females with reproductive potential, pregnancy tests should be performed before starting therapy, every month while it is being administered, and one month following the last dosage.
  • To prevent pregnancy both while receiving therapy and for at least a month after the final dose, effective contraceptive methods must be utilised.
  • An intrauterine device, a contraceptive implant, tubal sterilisation, or a combination of treatments, such as a hormonal contraceptive combined with one barrier method or two barrier methods, are available as contraceptive options.
  • In addition to the partner's vasectomy, a hormonal contraceptive (or barrier form of contraception) must be utilised.
  • All females must receive pregnancy prevention advice, and they must inform the prescriber if they become pregnant.

Macitentan use during breastfeeding:

• The excretion of the drug into breastmilk is not known.
• The manufacturer recommends discontinuing either the drug or breastfeeding weighing the risks and the benefits of the treatment.

Macitentan (Opsumit) Dose in Kidney Disease:

• The manufacturer has not recommended any adjustments in the dose.
• However, dose reduction is not required.
• The Canadian labeling recommends avoiding its use in patients who are on dialysis.

Macitentan (Opsumit) Dose in Liver disease:

• US labeling:

  • The manufacturer has not recommended any adjustments in the dose in patients with liver disease.

• Canadian labeling:

  • Baseline ALT or AST greater than thrice the upper limits of normal:
    • Do not initiate treatment.
  • Mild hepatic impairment:
    • No dose adjustment is necessary.
  • Moderate to severe hepatic impairment:
    • Avoid its use.

Common Side Effects of Macitentan (Opsumit):

• Central nervous system:

  • Headache

• Hematologic & oncologic:

  • Anemia

• Respiratory:

  • Nasopharyngitis
  • Pharyngitis
  • Bronchitis

Less Common Side Effects of Macitentan (Opsumit):

• Genitourinary:

  • Urinary tract infection

• Hematologic & oncologic:

  • Decreased hemoglobin

• Hepatic:

  • Increased liver enzymes

• Infection:

  • Influenza

Contraindications to Macitentan (Opsumit):

• Pregnancy
• Breastfeeding
• Allergic reactions to the drug or any component of the formulation.

Warnings and Precautions

• Fluid retention and peripheral edema:

  • Treatment or the underlying disease can cause peripheral edema that may require diuretics, fluid restriction and hospitalization.
  • Before deciding to continue/ discontinue the treatment, further evaluation may be required to determine the cause.
  • In patients with sever left ventricular dysfunction, it should be used with caution.

• Hematologic effects:

  • Hemoglobin and hematocrit reduction has been observed with its use.
  • Hematologic effects may occur early after treatment initiation and may require transfusions and stabilization.
  • Before the treatment is initiated, measure hemoglobin and repeat as clinically indicated.
  • In patients with severe anemia, avoid using the drug.

• Hepatic effects:

  • Hepatotoxicity and liver failure can occur manifesting as raised liver enzymes.
  • Monitor for the clinical features of hepatotoxicity. Monitor liver enzymes before treatment initiation and as clinically indicated.
  • Patients who develop hepatotoxicity (elevated liver enzymes with either elevated bilirubin greater than twice the upper limits of normal or clinical features of hepatotoxicity such as anorexia, fatigue, fever, dark urine, jaundice, itching, nausea, vomiting, and right upper quadrant pain) should discontinue treatment.
  • Once the liver functions normalize, treatment may be reinitiated if the patient does not have any clinical signs of hepatotoxicity.

• Spermatogenesis:

  • Male patients should be counseled regarding the effects of the drug on sperm counts and male fertility issues as it can result in a reduction in sperm counts.

• Pulmonary Veno-occlusive disease (PVOD):

  • Patients who develop the clinical features of pulmonary edema should be investigated for PVOD.
  • If PVOD is confirmed, treatment with macitentan should be discontinued.

Macitentan: Drug Interaction

Monitoring parameters:

• Observe and assess any peripheral edoema if it develops.
• Prior to starting a course of treatment and as clinically necessary, monitor liver enzyme levels.
• According to other specialists, liver enzymes should be checked regularly for the first year and thereafter as needed for clinical purposes.
• Keep an eye out for signs of hepatotoxicity (anorexia, abdominal pain, dark urine, fever, itching, jaundice, nausea, and vomiting).
• Before starting a course of treatment and when clinically required, monitor haemoglobin and hematocrit. When a patient has severe anaemia, avoid.
• Pregnancy tests for female patients should be performed before the start of treatment, once per month while receiving treatment, and one month after the final dosage.

How to administer Macitentan (Opsumit)?

• It is administered orally.
• The tablets should be swallowed whole.
• It should not be crushed, split, or chewed.
• The tablets may be administered with or without food.

Mechanism of action of Macitentan (Opsumit):

• It binds to endothelin receptors (ET-A and ET-B) present on the vascular endothelium and smooth muscles and inhibits their binding to endothelin-1.
• Inhibition of endothelin receptors results in vasodilation and inhibition of inflammation, fibrosis, smooth muscle proliferation, and hypertrophy.

Plasma Protein binding:

• >99% primarily to albumin

Metabolism:

• It is metabolized by the liver via CYP3A4 (major) and CYP2C19 to its active metabolite

Half-life elimination:

• About 16 hours (active metabolite: ~48 hours)

Time to peak plasma concentration:

• 8 hours

Excretion:

• Urine (~50%);
• feces (~24%)

International Brands of Macitentan:

• Opsumit
• Opsumite
• Zependo

Macitentan Brand Names in Pakistan:

No Brands Available in Pakistan.