Apbravi (Tablets) Instructions for Use

ATC Code

B01AC27 (Selexipag)

Active Substance

Selexipag (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Selective prostacyclin receptor agonist. A drug for the treatment of pulmonary hypertension

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

It is a selective agonist of prostacyclin (IP) receptors, different from prostacyclin and its analogs, and is hydrolyzed by carboxylesterases to form an active metabolite, the activity of which is approximately 37 times higher than the activity of the parent substance.

The active substance and its active metabolite are high-affinity agonists of IP receptors with high selectivity for IP receptors compared to other prostanoid receptors (EP₁-EP₄, DP, FP, and TP).

Selectivity for EP₁, EP₃, FP, and TP receptors is important because these receptors are responsible for contractile activity in the gastrointestinal tract and blood vessels.

Selectivity for EP₂, EP₄, and DP₁ receptors is important because these receptors mediate immunosuppressive effects.

Stimulation of IP receptors by the active substance and its active metabolite leads to vasodilation, as well as antiproliferative and antifibrotic effects.

The active substance prevents heart and lung remodeling in rats with pulmonary arterial hypertension (PAH) and causes a proportional decrease in pulmonary and peripheral pressure, showing that peripheral vasodilation reflects pharmacodynamic efficacy on pulmonary vessels.

Pharmacokinetics

Selexipag is rapidly absorbed and hydrolyzed by carboxylesterases to its active metabolite.

C_max in plasma after oral administration is reached within 1-3 hours and 3-4 hours. The absolute bioavailability is about 49%.

This is most likely a consequence of the first-pass effect of selexipag through the liver, as the plasma concentrations of the active metabolite are similar after oral and intravenous administration.

AUC after a single 400 mcg dose taken with food increases by 10% in Caucasians and decreases by 15% in Japanese subjects, while the exposure of the active metabolite decreases by 27% (in Caucasians) and 12% (in Japanese subjects).

Adverse events are observed more frequently when the drug is taken on an empty stomach compared to administration with food.

Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in total and equally to albumin and alpha-1 acid glycoprotein).

The V_d of selexipag at steady state is 11.7 L.

It is hydrolyzed to the active metabolite by carboxylesterases in the liver and intestine.

Oxidative metabolism, catalyzed mainly by the isoenzyme CYP2C8 and to a lesser extent by the isoenzyme CYP3A4, leads to the formation of hydroxylated and dealkylated products.

The isoenzymes UGT1A3 and UGT2B7 are involved in the conjugation of the active metabolite with glucuronic acid.

With the exception of the active metabolite, the concentration of each metabolite in plasma does not exceed 3% of the total drug-related material.

In healthy volunteers and patients with PAH after oral administration, the AUC of the active metabolite at steady state is approximately 3-4 times higher compared to the parent drug.

Elimination occurs primarily through metabolism with a mean terminal T_1/2 of 0.8-2.5 hours.

The T_1/2 of the active metabolite is 6.2-13.5 hours.

The total clearance of selexipag is 17.9 L/h.

Complete elimination is observed 5 days after drug intake and occurs primarily through the intestine (accounting for 93% of the administered dose) compared to renal excretion (12%).

Indications

Long-term treatment of pulmonary arterial hypertension in adult patients.

ICD codes

Dosage Regimen

Take orally twice daily, morning and evening, with food to reduce gastrointestinal adverse reactions.

Initiate treatment at 200 mcg twice daily.

Increase the dose in increments of 200 mcg twice daily, typically at weekly intervals, based on individual tolerability.

The maximum recommended maintenance dose is 1600 mcg twice daily.

If dose escalation is not tolerated due to adverse effects, reduce the dose to the previously tolerated level.

For patients with moderate hepatic impairment (Child-Pugh class B), administer the drug once daily and titrate more slowly.

Do not use in patients with severe hepatic impairment (Child-Pugh class C).

Use with caution in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²); titrate dose cautiously.

Consider dose adjustment when initiating or discontinuing concomitant therapy with moderate CYP2C8 inhibitors (e.g., clopidogrel).

Avoid concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil).

If a dose is missed, take the next dose at the scheduled time; do not double the dose to make up for a missed one.

Do not abruptly discontinue treatment; a gradual dose reduction may be considered under medical supervision.

Adverse Reactions

From the hematopoietic system common – anemia, decreased hemoglobin.

From the endocrine system common – hyperthyroidism, decreased concentration of thyroid-stimulating hormone (TSH) in the blood.

From the metabolism common – decreased appetite, weight loss.

From the CNS very common – headache.

From the cardiovascular system very common – flushing of the face and upper body; common – arterial hypotension; uncommon – sinus tachycardia.

From the respiratory system, thoracic and mediastinal organs very common – nasopharyngitis (non-infectious); common – nasal congestion.

From the digestive system very common – diarrhea, vomiting, nausea; common – abdominal pain.

From the skin and subcutaneous tissues common – rash, urticaria, erythema.

From the musculoskeletal system very common – jaw pain, myalgia, arthralgia, pain in extremities.

Contraindications

Hypersensitivity, severe coronary artery disease or unstable angina, myocardial infarction within the previous 6 months, decompensated heart failure in the absence of close medical supervision, severe cardiac arrhythmias, cerebrovascular diseases (e.g., transient ischemic attack, stroke) within the previous 3 months, congenital or acquired heart defects with clinically significant impairment of myocardial function not associated with pulmonary arterial hypertension, concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil), pregnancy and breastfeeding, children under 18 years of age.

With caution

In patients with arterial hypotension, in patients with pulmonary veno-occlusive disease, with concomitant use of moderate inhibitors of the CYP2C8 isoenzyme (e.g., clopidogrel, deferasirox, teriflunomide), in patients over 75 years of age, in patients with severe hepatic impairment (Child-Pugh class C), in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), in patients with hyperthyroidism, and in women of childbearing age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

The drug is contraindicated for use in severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

The drug is contraindicated for use in severe renal impairment (eGFR <30 mL/min/1.73 m²).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is contraindicated for use in elderly patients over 75 years of age.

Special Precautions

The medicinal product has vasodilating properties that may lead to a decrease in blood pressure in the vessels.

Before prescribing, a thorough assessment should be made whether certain pathological conditions in the patient may worsen due to the vasodilatory effects of selexipag (e.g., in patients receiving antihypertensive therapy, patients with resting arterial hypotension, hypovolemia, severe left ventricular outflow tract obstruction, or autonomic dysfunction).

Some patients may experience hyperthyroidism.

If signs and symptoms of hyperthyroidism appear, appropriate thyroid function tests are recommended.

Cases of pulmonary edema have been reported with the use of vasodilators (mainly prostacyclin derivatives) in patients with pulmonary veno-occlusive disease.

Therefore, if signs of pulmonary edema appear in patients with PAH, the patient should be examined for pulmonary veno-occlusive disease.

If the diagnosis is confirmed, treatment should be discontinued.

Concomitant use with moderate inhibitors of the CYP2C8 isoenzyme (clopidogrel, deferasirox, teriflunomide) may lead to an increase in the AUC of selexipag and its active metabolite.

A dose adjustment should be considered when co-administering a moderate CYP2C8 isoenzyme inhibitor or upon its discontinuation.

Experience in patients over 75 years of age is limited, therefore it should be prescribed with caution in this group of patients.

There is no experience with the use of selexipag in patients with severe hepatic impairment (Child-Pugh class C), therefore the drug is not indicated for the treatment of this group of patients.

The AUC of the active substance and its active metabolite is increased in patients with moderate hepatic impairment (Child-Pugh class B).

In patients with moderate hepatic impairment, it should be applied once a day.

Dose titration in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) should be performed with caution.

There is no experience in patients on hemodialysis, therefore Selexipag is not recommended for use in this group of patients.

Effect on ability to drive vehicles and machinery

During treatment, patients should avoid driving vehicles and other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

CYP2C8 isoenzyme inhibitors

Concomitant use of gemfibrozil, a strong CYP2C8 isoenzyme inhibitor, twice daily increases the AUC of selexipag approximately two-fold, while the AUC of the active metabolite, which exerts the main pharmacological effect, increases approximately 11-fold.

Concomitant use with strong CYP2C8 isoenzyme inhibitors (gemfibrozil) is contraindicated.

CYP2C8 isoenzyme inducers

Concomitant use of rifampicin, an inducer of the CYP2C8 isoenzyme (and enzymes of the UDP-glucuronosyltransferase (UGT) group), once daily does not affect the AUC, but leads to a 2-fold decrease in the AUC of its active metabolite.

A dose adjustment may be required when co-administered with CYP2C8 isoenzyme inducers (rifampicin, carbamazepine, phenytoin).

PAH-specific therapy

In combination with endothelin receptor antagonists and PDE5 inhibitors, it leads to a 30% decrease in the AUC of the active metabolite of selexipag.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.