Opsumit

Macitentan instruction manual
Common name: Macitentan
Trade name: opsumit
All names: Macitentan, opsumit, macitentan, Masitentan

Indications:
Aoposil is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the disease progression and risk of hospitalization in PAH.

Usage and dosage:
The recommended oral dosage is 10 mg, once a day.
Can be taken with or without food. Patients are not advised to break the tablets in half, crush them, or chew them.
Doses higher than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension and are not recommended.

Adverse reactions:
Clinically significant adverse reactions include: embryo-fetal toxicity; hepatotoxicity; fluid retention; hemoglobin reduction.
Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed for one drug in clinical trials cannot be directly compared to the rates observed for another drug in clinical trials, nor do they reflect the rates observed in clinical practice.
The safety data of this product mainly come from a placebo-controlled clinical study (SERAPHIN study) conducted in 742 patients with pulmonary arterial hypertension. In this trial, exposure to this product lasted up to 3.6 years, with a median exposure time of approximately 2 years (1 year: N=542; 2 years: N=429; >3 years: N=98). The overall incidence of treatment discontinuation due to adverse events was similar between the groups receiving macitentan 10 mg and the placebo group (approximately 11%). The following shows adverse reactions that occurred more frequently than 3% in the group receiving macitentan compared with the placebo group:
N=242 in the macitentan 10 mg group and N=249 in the placebo group.
Anemia: 13% in the macitentan group and 3% in the placebo group.
Nasopharyngitis/pharyngitis: 20% in the macitentan group and 13% in the placebo group.
Bronchitis: 12% in the macitentan group and 6% in the placebo group.
Headache: 14% in the macitentan group and 9% in the placebo group.
Influenza: 6% in the macitentan group and 2% in the placebo group.
Urinary tract infection: 9% in the macitentan group and 6% in the placebo group.

Post-marketing experience: The following adverse reactions have been identified during post-approval use of this product. Because these reactions are reported spontaneously from a population of unknown sample size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Various immune system diseases: Hypersensitivity reactions (angioedema, pruritus and rash).
Respiratory system, chest and mediastinal diseases: nasal congestion.
Gastrointestinal Disorders: Elevated hepatic aminotransferases (ALT, AST) and liver injury have been reported during administration of this product; alternative causes (heart failure, hepatic congestion, autoimmune hepatitis) have been identified in most cases. Endothelin receptor antagonists (ERA) are known to be associated with elevated transaminases, hepatotoxicity, and cases of liver failure.
Systemic diseases and various reactions at the administration site: edema/fluid retention. Adverse effects of edema and fluid retention occur within a few weeks of taking this product, some requiring diuretics, fluid management, or hospitalization to treat decompensated heart failure.
Heart disease: Symptomatic hypotension.

Contraindications:
Contraindicated for pregnant women.
If this drug is taken during pregnancy, patients should be informed of the possible harm to the fetus.

Note:
Embryo-fetal toxicity
Taking Aoposil during pregnancy may cause harm to the fetus and is prohibited from use in pregnant women. For females of childbearing potential, rule out pregnancy before initiating treatment, ensure that an acceptable method of contraception is used, and obtain monthly pregnancy tests.
Opsumit is available to women through the Opsumit REMS plan (Restricted Distribution Plan).
Opsumit REMS Program (Restricted Distribution Program)
For all women, Opsumit is only available through a restricted program called the Opsumit REMS Program because of the risk of embryotoxicity.
Notable requirements for the Opsumit REMS program include: Prescribers must become certified in the course by enrolling and completing training.
All women, regardless of their reproductive potential, must enroll in the Opsumit REMS program before using Opsumit. Male patients do not participate in REMS.
Women of childbearing potential must comply with pregnancy testing and contraceptive requirements.
Pharmacies must be certified by the program and must dispense only to patients who are entitled to receive oral contraceptives.
Hepatotoxicity
Aposil can cause elevated transaminases, hepatotoxicity, and liver failure.
In placebo-controlled studies, the discontinuation rate of hepatic adverse events was 3.3% in the oral Proposil 10 mg group compared with 1.6% in the placebo group.
Perform liver enzyme testing before initiating treatment and repeat during treatment as clinically indicated.
Advise patients to report symptoms of liver injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant transaminase elevations occur, or if accompanied by an increase in bilirubin >2 x ULN (upper line of normal), or an increase in clinical signs of hepatotoxicity, discontinue use of Aoposil. Consider reinitiating Aoposil when liver enzyme levels normalize in patients who do not experience clinical signs of hepatotoxicity.
Fluid Retention
Peripheral edema and fluid retention are known clinical consequences of ERA (Endothelin Receptor Antagonists) and known effects of endothelin receptor antagonists. In a controlled study of complement in PAH (pulmonary arterial hypertension), the incidence of edema was 21.9% in the complement 10 mg group and 20.5% in the placebo group.
Patients with underlying left ventricular dysfunction may be at particular risk for significant fluid retention after initiating ERA (endothelin receptor antagonist) therapy. In a study of patients with pulmonary hypertension due to left ventricular dysfunction, more patients had significant fluid retention and more patients were hospitalized for worsening heart failure than in the randomized placebo group. There have been reports of edema and fluid retention within weeks of starting oral Aposil, with some patients requiring diuretic intervention or hospitalization for decompensated heart failure. Monitor for signs of fluid retention after initiating use of APCOS. If clinically significant fluid retention occurs, evaluate the patient to determine the etiology, such as underlying heart failure, and discontinuation of Aoposil may be necessary.
Decrease in Hemoglobin
Decreases in hemoglobin concentration and hematocrit have occurred after taking other eras (endothelin receptor antagonists) and have been observed in clinical studies with Aoposil. These declines occurred early and stabilized thereafter. In placebo-controlled studies of complement in PAH (pulmonary arterial hypertension), complement 10 mg resulted in an average decrease in hemoglobin of approximately 1.0 g/dL from baseline to 18 months, with no change in the placebo group. It was reported that the proportion of hemoglobin falling below 10.0 g/dL was 8.7% in the 10 mg Apovasil group and 3.4% in the placebo group. A decrease in hemoglobin rarely requires a blood transfusion. Patients with severe anemia are not recommended to use Aoposil. Measure hemoglobin before starting treatment and repeat measurements during treatment.
Pulmonary edema with pulmonary veno-occlusive disease (PVOD)
If signs of pulmonary edema are present, consider the possibility of associated PVOD. If confirmed, stop using AUPOS.
Reduced Sperm Count
Other endothelin receptor antagonists may have serious adverse effects on spermatogenesis. Male patients should be informed of the potential effects of this drug on fertility.

Storage:
Save below 30℃.

Mechanism of action:
Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to ETA and ETB receptors. Macitentan shows high affinity and persistence of ET receptors in human pulmonary artery smooth muscle cells. A metabolite of Macitentan also has pharmacological activity at the ET receptor, and its in vitro potency is estimated to be approximately 20% of the parent drug. The clinical impact of dual endothelin blockade is unknown.

Safety and Efficacy:
The PORTICO trial demonstrated that the safety, including hepatic safety, of macitentan in patients with portal hypertension-associated pulmonary hypertension (POPH) was consistent with results observed in previous clinical trials.
In the PORTICO study, patients were randomized to receive macitentan 10 mg (n = 43) or placebo (n = 42) once daily. After 12 weeks of treatment, macitentan significantly improved pulmonary vascular resistance (PVR, meeting the primary endpoint, 35% lower in the macitentan group than placebo, p < 0.0001), mean pulmonary arterial pressure (mPAP; 5.99 mmHg lower in the macitentan group than placebo, p < 0.0001), and cardiac index (0.52 L/min/m2 higher in the macitentan group than placebo, p = 0.0009).
There were no significant differences in 6-minute walking distance (6MWD) or WHO functional class (FC) between the macitentan and placebo groups. The most common adverse events were peripheral edema (25.6% and 11.9% in the macitentan group and placebo group, respectively) and headache (16.3% and 16.7%).
Macitentan is a new dual endothelin receptor antagonist (ERA) with high tissue affinity. Aoposhu has obtained approval numbers from drug regulatory authorities in 59 countries, including China (China Import Drug Registration Certificate Number: H20170376).