Respitrol^® (Capsules) Instructions for Use

Marketing Authorization Holder

PSK Pharma, LLC (Russia)

ATC Code

R03AC18 (Indacaterol)

Active Substance

Indacaterol (Rec.INN registered by WHO)

Dosage Forms

	Respitrol®	Powder for inhalation capsules 150 mcg
		Powder for inhalation capsules 300 mcg

Dosage Form, Packaging, and Composition

Powder for inhalation capsules

10 pcs. – blister packs – cardboard packs /complete with an inhaler/ – Prescription only
10 pcs. – blister packs (3 pcs.) – cardboard packs /complete with an inhaler/ – Prescription only
10 pcs. – blister packs (9 pcs.) – cardboard packs /complete with an inhaler/ – Prescription only

Powder for inhalation capsules

10 pcs. – blister packs – cardboard packs /complete with an inhaler/ – Prescription only
10 pcs. – blister packs (3 pcs.) – cardboard packs /complete with an inhaler/ – Prescription only
10 pcs. – blister packs (9 pcs.) – cardboard packs /complete with an inhaler/ – Prescription only

Clinical-Pharmacological Group

Bronchodilator drug – beta₂-adrenergic agonist

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases. Adrenergics for inhalation administration. Selective beta2-adrenergic agonists

Pharmacological Action

It is a selective long-acting beta₂-adrenergic receptor agonist (for 24 hours) with a single dose. The pharmacological action of beta₂-adrenergic receptor agonists, including Indacaterol, is associated with the stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cyclic 3′,5′-adenosine monophosphate (cyclic AMP). The increase in cyclic AMP levels leads to the relaxation of bronchial smooth muscles. Indacaterol is an almost full agonist of beta₂-adrenergic receptors; the stimulatory effect of the drug on beta₂-adrenergic receptors is 24 times stronger than on beta₁-adrenergic receptors, and 20 times stronger than on beta₃-adrenergic receptors.

Indacaterol provides sustained significant improvement in lung function (increase in FEV₁) over 24 hours.

Indacaterol reduces dynamic and static hyperinflation (increase in lung volumes at the end of spontaneous expiration) in patients with moderate to severe COPD. A statistically significant increase in inspiratory capacity and FEV₁, a reduction in dyspnea, and an improvement in exercise tolerance are observed. There is also a significant reduction in the risk of COPD exacerbations (increased time to the next exacerbation), a reduced need for short-acting inhaled beta₂-adrenergic receptor agonists, and an improvement in the quality of life of patients.

It is characterized by a rapid onset of action (within 5 minutes after inhalation), comparable to the effect of salbutamol, a short-acting beta₂-adrenergic receptor agonist. The maximum effect of indacaterol is noted 2-4 hours after inhalation. In patients treated with Indacaterol for 1 year, no development of tachyphylaxis to the bronchodilatory effect was observed. When using indacaterol, no dependence of the bronchodilatory effect on the time of inhalation during the day (morning or evening) was identified.

Pharmacokinetics

After single or repeated inhalations, the average time to reach C_max of indacaterol in blood serum is about 15 minutes. The systemic exposure of indacaterol increases with increasing dose (in the range from 150 mcg to 600 mcg) and is dose-dependent. After a single inhalation, the absolute bioavailability of indacaterol is about 43%. Systemic exposure is the result of drug absorption in the lungs and intestines. The concentration of indacaterol in blood serum increases with repeated use of the drug. C_ss is reached after 12-15 days of drug use. With indacaterol inhalation once daily (in doses from 75 mcg to 600 mcg) for 14 days, the accumulation factor of indacaterol, estimated by the exposure of indacaterol on day 1 and day 14 or 15 (AUC_0-24), ranges from 2.9 to 3.8.

After IV administration, the V_d of indacaterol was 2.361-2.557 L, indicating significant distribution. Binding to human serum and plasma proteins is 94.1-95.3% and 95.1-96.2%, respectively.

Upon oral administration of radiolabeled indacaterol, unchanged Indacaterol is the main component in serum and accounts for approximately 1/3 of the total drug-related AUC_0-24. Among the metabolites of indacaterol in blood serum, the hydroxylated derivative of indacaterol is the most prominent. Next, hydroxylated Indacaterol and the phenolic O-glucuronide of indacaterol predominate. Later, diastereomers of the hydroxylated derivative, the N-glucuronide of indacaterol, and C- and N-dealkylated products are detected. UDP-glucuronosyltransferase (UGT1A1) is the only isoenzyme that metabolizes Indacaterol to the phenolic O-glucuronide. Hydroxylation of indacaterol occurs mainly with the help of the CYP3A4 isoenzyme. It has also been established that Indacaterol is a substrate for the membrane transporter P-glycoprotein (P-gp), but has low affinity.

The amount of unchanged indacaterol excreted in the urine is less than 2% of the dose. The renal clearance of indacaterol averaged 0.46-1.20 L/h. Given that the serum clearance of indacaterol is 18.8-23.3 L/h, it is clear that renal excretion is insignificant (approximately 2-5% of systemic clearance).

Upon oral administration, Indacaterol was excreted mainly through the intestine (90% of the dose): unchanged (54% of the dose) and as hydroxylated metabolites (23% of the dose).

The concentration of indacaterol in blood serum decreases stepwise with a mean terminal T_1/2 in the range of 45.5 to 126 hours. The T_1/2, calculated based on the accumulation of indacaterol after repeated use, varied from 40 to 56 hours, which was consistent with the established time to reach steady state (12-14 days).

Indications

Long-term maintenance therapy of bronchial obstruction disorders in patients with COPD.

ICD codes

Dosage Regimen

Administer Respitrol^® by oral inhalation once daily at the same time each day.

The recommended starting and maintenance dose is 150 mcg (one capsule).

For some patients, particularly those with severe COPD, a dose of 300 mcg (one capsule) once daily may provide additional clinical benefit.

Do not exceed the maximum daily dose of 300 mcg.

Use only with the specific inhaler device provided. Do not swallow the capsules.

Inspect the capsule immediately before use. Use only if it is undamaged.

Pierce the capsule only once, immediately before inhalation.

Inhale the contents of the capsule rapidly and forcefully.

If a dose is missed, take it as soon as remembered on the same day. Do not double the next dose to make up for a missed one.

This is a maintenance bronchodilator. Do not use for the relief of acute bronchospasm or asthma attacks.

Adverse Reactions

Infections and infestations very common – nasopharyngitis, upper respiratory tract infections; common – sinusitis.

Respiratory system disorders common – cough, sore throat, rhinorrhea, throat irritation; uncommon – paradoxical bronchospasm.

Skin and subcutaneous tissue disorders common – rash, itching.

Musculoskeletal system disorders common – muscle spasm, bone pain; uncommon – myalgia.

Nervous system disorders common – dizziness; uncommon – paresthesia.

Cardiovascular system disorders common – coronary artery disease; uncommon – atrial fibrillation, tachycardia.

Digestive system disorders common – dry mouth.

Metabolism disorders common – hyperglycemia, newly diagnosed diabetes mellitus.

General disorders common – peripheral edema, chest pain (non-cardiac); uncommon – chest discomfort.

Contraindications

Age under 18 years (efficacy and safety not established); pregnancy, lactation (breastfeeding); hypersensitivity to indacaterol.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Do not use for the relief of acute bronchospasm.

Use with caution in patients with concomitant cardiovascular disorders (coronary artery disease, acute myocardial infarction, arrhythmias, arterial hypertension), with convulsive disorders, thyrotoxicosis, diabetes mellitus, as well as in patients with a history of inadequate response to the action of beta₂-adrenergic receptor agonists.

If there are signs indicating the development of an allergic reaction (in particular, difficulty breathing or swallowing, swelling of the tongue, lips and face, urticaria, skin rash), Indacaterol should be discontinued and alternative therapy selected.

Like any other inhalation therapy, the use of indacaterol can lead to the development of paradoxical bronchospasm, which is life-threatening. In the event of paradoxical bronchospasm, treatment with indacaterol should be stopped immediately and alternative therapy prescribed.

A decrease in serum potassium concentration is usually transient and does not require correction. In patients with severe COPD, hypokalemia may be exacerbated by hypoxia and concomitant therapy, which, in turn, may increase the likelihood of arrhythmias.

When using indacaterol in patients with diabetes mellitus, blood glucose levels should be regularly monitored.

Drug Interactions

With simultaneous use with drugs that prolong the QT interval, this effect may be enhanced. Use with caution in patients receiving MAO inhibitors, tricyclic antidepressants, or other drugs that prolong the QT interval. Prolongation of the QT interval increases the risk of ventricular tachycardia.

Concomitant use of indacaterol with sympathomimetics (either separately or as part of combination therapy) may increase the risk of adverse events. It should not be used concurrently with other long-acting beta₂-adrenergic receptor agonists or with medicinal products containing long-acting beta₂-adrenergic receptor agonists.

Concomitant use with methylxanthine derivatives, corticosteroids, or potassium-excreting diuretics may enhance the possible hypokalemia caused by beta₂-adrenergic receptor agonists.

Since beta₂-adrenergic receptor blockers may weaken the effect or prevent the action of beta₂-adrenergic receptor agonists, Indacaterol should not be used simultaneously with beta₂-adrenergic receptor blockers (including eye drops).

Concomitant use of indacaterol with verapamil led to a 1.4-2-fold increase in AUC and a 1.5-fold increase in C_max. When using indacaterol with erythromycin, an increase in AUC of 1.4-1.6 times and C_max of 1.2 times was observed. Combination therapy with indacaterol and ketoconazole caused a 2-fold and 1.4-fold increase in AUC and C_max, respectively. This increase in exposure due to drug interaction did not lead to a change in the safety profile. With simultaneous use of indacaterol with ritonavir (an inhibitor of the CYP3A4 isoenzyme and P-glycoprotein), an increase in AUC of 1.6-1.8 times was noted, but C_max remained unchanged.

In vitro studies have shown that Indacaterol has a low potential for interaction with drugs at the level of enzyme metabolism or at the level of membrane transporters at systemic exposure achieved at therapeutic doses.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.