Enerzair Breezhaler^® (Capsules) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Pharma Stein AG (Switzerland)

Or

Sigfried Barbera, S.L. (Spain)

Labeled By

SIGFRIED BARBERA, S.L. (Spain)

Quality Control Release

NOVARTIS FARMACEUTICA, S.A. (Spain)

Contact Information

NOVARTIS PHARMA LLC (Russia)

ATC Code

R03AL12 (Indacaterol, glycopyrronium bromide and mometasone)

Active Substances

Mometasone (Rec.INN registered by WHO)

Indacaterol (Rec.INN registered by WHO)

Glycopyrronium bromide (Rec.INN registered by WHO)

Dosage Forms

	Enerzair Breezhaler®	Powder for inhalation capsules 50 mcg+150 mcg+80 mcg: 10 or 30 pcs. in a kit with an inhalation device (Breezhaler®)
		Powder for inhalation capsules 50 mcg+150 mcg+160 mcg: 10 or 30 pcs. in a kit with an inhalation device (Breezhaler®)

Dosage Form, Packaging, and Composition

Powder for inhalation capsules (dosage 50 mcg+150 mcg+80 mcg) hard, size No. 3, with a transparent green cap and a transparent colorless body, with marking; capsule contents: white or almost white powder; marking (radial): on the cap – a white ” logo; on the body – the inscription “IGM150-50-80” in black.

Excipients : lactose monohydrate, magnesium stearate.

Capsule shell composition: hypromellose, purified water, carrageenan, potassium chloride, iron oxide yellow (E172), indigo carmine (E132), black ink, white ink.
Black ink composition purified water, iron oxide black (E172), isopropanol, propylene glycol (E1520), hypromellose (E464).
White ink composition purified water, titanium dioxide (E171), isopropanol, propylene glycol (E1520), hypromellose (E464).

10 pcs. – blisters made of PA/Al/PVC and PET/Al (Al/Al) (1) in a kit with an inhalation device (Breezhaler^®) – cardboard packs.
10 pcs. – blisters made of PA/Al/PVC and PET/Al (Al/Al) (3) in a kit with an inhalation device (Breezhaler^®) – cardboard packs.

Powder for inhalation capsules (dosage 50 mcg+150 mcg+160 mcg) hard, size No. 3, with a transparent green cap and a transparent colorless body, with marking; capsule contents: white or almost white powder; marking (radial): on the cap – a black ” logo, surrounded by a black stripe; on the body – the inscription “IGM150-50-160” in black, located above a double black stripe.

Excipients : lactose monohydrate, magnesium stearate.

Capsule shell composition: hypromellose, purified water, carrageenan, potassium chloride, iron oxide yellow (E172), indigo carmine (E132), black ink, white ink.
Black ink composition purified water, iron oxide black (E172), isopropanol, propylene glycol (E1520), hypromellose (E464).

10 pcs. – blisters made of PA/Al/PVC and PET/Al (Al/Al) (1) in a kit with an inhalation device (Breezhaler^®) – cardboard packs.
10 pcs. – blisters made of PA/Al/PVC and PET/Al (Al/Al) (3) in a kit with an inhalation device (Breezhaler^®) – cardboard packs.

The presence of primary opening control on the cardboard pack is allowed.

Clinical-Pharmacological Group

Bronchodilator combination drug (selective beta₂-adrenergic agonist + m-cholinoreceptor blocker + glucocorticosteroid)

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases, adrenergics in combination with anticholinergics and glucocorticosteroids

Pharmacological Action

Mechanism of action

The drug Enerzair Breezhaler^® is a combination of indacaterol, a long-acting beta₂-adrenergic agonist (LABA), glycopyrronium, a long-acting anticholinergic drug (LAMA), and mometasone furoate, an inhaled synthetic glucocorticosteroid (GCS).

Indacaterol. The pharmacological action of beta₂-adrenergic agonists, including indacaterol, is at least partially due to the stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) into cyclic 3′,5′-adenosine monophosphate (cAMP). Increased cAMP levels lead to relaxation of bronchial smooth muscle.

When inhaled, indacaterol acts locally on the lungs as a bronchodilator. Indacaterol is a partial agonist of human β₂-adrenergic receptors with nanomolar activity. In studies on isolated human bronchi, indacaterol has a rapid and long-lasting effect.

Although β₂-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle, and β₁-receptors predominate in the human heart, β₂-adrenergic receptors nevertheless account for 10-50% of the total number of adrenergic receptors in the human heart.

Glycopyrronium – an inhaled long-acting muscarinic antagonist (LAMA). The mechanism of action of glycopyrronium is based on blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, leading to a bronchodilatory effect. Five subtypes of muscarinic receptors (M_1-5) have been identified in the human body. It is known that only the M_1-3 subtypes are involved in the physiological function of the respiratory system. Glycopyrronium has a high affinity for these receptor types, and it has 4-5 times greater selectivity for M₁ and M₃ receptors compared to M₂ receptors. Glycopyrronium causes a rapid onset of effect, as evidenced by the kinetic parameters of receptor association-dissociation and the time to onset of therapeutic effect observed in clinical trials (CT). The long duration of action of glycopyrronium may be partly explained by the long period of maintenance of its therapeutic concentration in the lungs, as confirmed by the longer T_1/2 of glycopyrronium after inhalation compared to T_1/2 after intravenous administration.

Mometasone furoate – a synthetic glucocorticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory effect. It has been established that inhalation of mometasone furoate in patients with bronchial asthma provides a favorable ratio of local action in the lungs and systemic exposure. A significant part of the mechanism of action of mometasone furoate appears to be based on its ability to inhibit the release of mediators of the inflammatory cascade. In vitro, Mometasone furoate inhibits the release of leukotrienes (LT) from leukocytes in allergic patients. In cell cultures, Mometasone furoate demonstrated a high ability to inhibit the synthesis and release of interleukins 1, 5 and 6 (IL-1, IL-5, IL-6), as well as tumor necrosis factor alpha (TNF-α). It is also an inhibitor of the production of LT Th2 cytokines, interleukins 4 and 5, synthesized by human CD4+ T-cells.

Pharmacodynamics

The primary pharmacodynamics of the drug Enerzair Breezhaler^® in obstructive airway pathology reflects the complementary mechanisms of action of the individual components.

Available clinical data support the hypothesis that the complementary bronchodilatory effect of indacaterol and glycopyrronium in combination with the anti-inflammatory action of mometasone furoate improves lung function and asthma control.

In clinical studies, the use of the fixed combination of indacaterol, glycopyrronium and mometasone furoate was associated with more favorable lung function parameters when using the drug Enerzair Breezhaler^® 150 mcg+50 mcg+80 mcg once daily and 150 mcg+50 mcg+160 mcg once daily compared to the fixed combination of salmeterol and fluticasone 50 mcg+500 mcg twice daily, the fixed combination of indacaterol and mometasone furoate 150 mcg+160 mcg and 150 mcg+320 mcg once daily, and placebo.

The pharmacodynamic response profile to therapy with the drug Enerzair Breezhaler^® is characterized by an onset of action within 5 minutes after inhalation and a duration of effect of more than 24 hours.

The pharmacodynamic response profile is characterized by an increase in the mean peak forced expiratory volume in 1 second (FEV₁), which is 172 ml and 159 ml after administration of the drug Enerzair Breezhaler^® 150 mcg+50 mcg+80 mcg and 150 mcg+50 mcg+160 mcg once daily, respectively, compared to the fixed combination of salmeterol and fluticasone 50 mcg+500 mcg, taken twice daily. No data indicating the development of tachyphylaxis to the drug Enerzair Breezhaler^® were obtained.

Effect on the QT_c interval

Specialized studies on the effect of the drug on the QT interval length (TQT) have not been conducted.

No properties of mometasone furoate that contribute to QT_c interval prolongation are known.

Clinical studies

In a clinical study of the use of the drug Enerzair Breezhaler^®, 150 mcg+50 mcg+80 mcg once daily and 150 mcg+50 mcg+160 mcg once daily, compared with the combination of salmeterol and fluticasone 50 mcg+500 mcg twice daily + tiotropium bromide 5 mcg once daily, demonstrated comparable efficacy in improving the quality of life of patients with bronchial asthma according to the Asthma Quality of Life Questionnaire (AQLQ).

The drug Enerzair Breezhaler^®, 150 mcg+50 mcg+80 mcg once daily and 150 mcg+50 mcg+160 mcg once daily, showed a favorable safety profile, comparable to therapy with salmeterol and fluticasone 50 mcg+500 mcg twice daily + tiotropium bromide 5 mcg once daily.

Pharmacokinetics

Absorption

After inhalation of the drug Enerzair Breezhaler^®, the mean T_max of indacaterol, glycopyrronium and mometasone furoate in plasma was approximately 15 minutes, 5 minutes and 1 hour, respectively.

Based on the results of in vitro studies, it was found that the dose of each component delivered to the lungs when using the drug Enerzair Breezhaler^® corresponds to that when these compounds are used separately. After inhalation of the drug Enerzair Breezhaler^®, the exposure of indacaterol, glycopyrronium and mometasone furoate at steady state in plasma did not differ from the systemic exposure of indacaterol maleate, glycopyrronium or mometasone furoate after their separate inhalation.

After inhalation of the drug Enerzair Breezhaler^®, the absolute bioavailability of indacaterol, glycopyrronium and mometasone furoate was about 45%, 40% and less than 10%, respectively.

Indacaterol

The concentration of indacaterol increases with repeated once-daily administration. The steady-state blood concentration (C_ss) is reached within 12-14 days of drug use. With inhaled administration in doses of 75 – 600 mcg once daily, the mean accumulation factor of indacaterol (i.e., AUC_{0-24 h} on day 14 compared to day 1) ranged from 2.9 to 3.8. Systemic exposure is the result of absorption of indacaterol in the lungs and gastrointestinal tract: about 75% of systemic exposure is provided by absorption in the lungs and about 25% in the gastrointestinal tract.

Glycopyrronium

After inhalation, about 90% of systemic exposure is provided by absorption in the lungs and 10% in the gastrointestinal tract. With oral administration, the estimated absolute bioavailability of glycopyrronium is 5% of the delivered dose.

Mometasone furoate

The concentration of mometasone furoate increases with repeated once-daily administration using the Breezhaler^® device. C_ss of the substance is reached after 12 days. With inhaled administration in doses of 80 and 160 mcg once daily as part of the drug Enerzair Breezhaler^®, the mean accumulation factor of mometasone furoate (i.e., AUC_{0-24 h} on day 14 compared to AUC_{0-24 h} on day 1) ranged from 1.28 to 1.40.

After oral administration of mometasone furoate, its estimated absolute bioavailability was very low (less than 2%).

Distribution

Indacaterol

After intravenous infusion, the volume of distribution (V_d) of indacaterol ranged from 2.361 to 2.557 L, indicating significant distribution of the drug. In vitro, approximately 94.1-95.3% and 95.1-96.2% of indacaterol is bound to human serum and plasma proteins, respectively.

Glycopyrronium

After intravenous administration, the steady-state volume of distribution (V_ss) of glycopyrronium was 83 L, and the terminal phase volume of distribution (V_z) reached 376 L. After inhalation, the apparent terminal phase volume of distribution (V_z/F) was 7310 L, reflecting its slower elimination after inhalation. In vitro, 38-41% of glycopyrronium is bound to human plasma proteins at concentrations of 1-10 ng/ml. These concentrations were at least 6 times higher than the mean maximum steady-state levels in plasma observed with the drug at a dose of 50 mcg once daily.

Mometasone furoate

After intravenous bolus administration, V_d is 332 L. The binding of mometasone furoate to plasma proteins in vitro is very high and is 98-99% at concentrations of 5-500 ng/ml.

Metabolism

Indacaterol

In an absorption, distribution, metabolism, and excretion (ADME) study after oral administration of radiolabeled indacaterol, unchanged indacaterol is the main component in serum and accounts for approximately one-third of the daily AUC. Of all the metabolites of indacaterol in serum, the highest content was determined for the hydroxylated derivative. Indacaterol phenolic O-glucuronide and hydroxylated indacaterol are found in smaller quantities. In addition, diastereomers of the hydroxylated derivative, indacaterol N-glucuronide, and C- and N-dealkylation products are detected.

In vitro studies have established that the UGT1A1 isoenzyme is the only UGT isoenzyme that metabolizes indacaterol to phenolic O-glucuronide. After incubation with recombinant CYP1A1, CYP2D6 and CYP3A4 isoenzymes, oxidative metabolites were identified. This means that the hydroxylation of indacaterol occurs mainly under the action of the CYP3A4 isoenzyme. Further in vitro studies established that indacaterol is a low-affinity substrate for the membrane transporter P-glycoprotein (Pgp). According to the results of in vitro studies, the metabolic clearance of indacaterol occurs mainly under the influence of the UGT1A1 isoform. However, according to the results of clinical studies in patient populations with different UGT1A1 isoform genotypes, this genotype does not have a significant effect on the systemic exposure of indacaterol.

Glycopyrronium

The results of in vitro metabolism studies indicate that the metabolic pathways of glycopyrronium in humans and animals do not differ. No metabolites specific only to humans have been identified. Hydroxylation of glycopyrronium leads to the formation of various mono- and bihydroxylated metabolites, and direct hydrolysis leads to the formation of carboxylic acid derivatives (M9). In vitro studies have shown that CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. Hydrolysis to M9 appears to be catalyzed by cholinesterase family enzymes. After inhalation, the systemic exposure of M9 on average did not differ from the exposure of the parent substance. Since in vitro studies did not reveal metabolism of the active substance in the lungs, and the contribution of M9 to circulation was minimal (4% of C_max and AUC of glycopyrronium) after intravenous administration, it is assumed that M9 is formed from the fraction of the active substance that entered through the gastrointestinal tract after inhalation through presystemic hydrolysis and/or during the “first pass” through the liver. After inhalation or intravenous administration, only a minimal amount of M9 was found in the urine (≤0.5% of the administered dose). Glucuronic and/or sulfate conjugates of glycopyrronium were found in human urine after repeated inhalations in an amount of approximately 3% of the delivered dose. In vitro inhibition studies have shown that glycopyrronium does not have a significant ability to inhibit the activity of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 isoenzymes, the transport proteins MDR1, MRP1 or MXR, which mediate the excretion of drugs from cells, or the transporter proteins OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. Enzyme induction studies in vitro did not reveal any clinically significant ability of glycopyrronium to induce cytochrome P450 isoenzymes, the UGT1A1 isoenzyme, or the MDR1 and MRP2 transporter proteins.

Mometasone furoate

The delivered dose of mometasone furoate that enters and is absorbed in the gastrointestinal tract is rapidly metabolized to various metabolites. The main metabolites are not detected in plasma. In human liver microsomes, the metabolism of mometasone furoate occurs under the action of the cytochrome P-450 3A4 isoenzyme (CYP3A4 isoenzyme).

Excretion

Indacaterol

In clinical studies with urine analysis, the amount of unchanged indacaterol excreted by the kidneys was generally less than 2% of the delivered 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 clearance plays a minor role (approximately 2-6% of systemic clearance) in the systemic elimination of indacaterol.

After oral administration, indacaterol was excreted mainly through the intestine: unchanged (54% of the delivered dose) and as hydroxylated metabolites (23% of the delivered dose). Complete mass balance was achieved with more than 90% recovery from excreta.

The concentration of indacaterol in serum decreases multiphasically with a mean terminal T_1/2 in the range of 45.5 to 126 hours. The effective T_1/2, calculated based on the accumulation of indacaterol after repeated administration, varied from 40 to 52 hours, which is consistent with the established time to reach steady state (12-14 days).

Glycopyrronium

After intravenous administration of 3H-labeled glycopyrronium to humans, an average of 85% of the delivered dose was excreted in the urine within 48 hours. Another 5% of the dose was found in the bile. Thus, the mass balance was almost complete.

Renal excretion of glycopyrronium accounts for 60-70% of the total plasma clearance, while 30-40% is eliminated by other routes – via bile or through metabolism. In healthy volunteers and patients with COPD who received glycopyrronium by inhalation in doses from 50 to 200 mcg once daily, both as a single dose and repeatedly, the mean renal clearance of glycopyrronium ranged from 17.4 to 24.4 L/h. The renal excretion of glycopyrronium is due to active tubular secretion. Up to 20% of the dose is found unchanged in the urine. The plasma concentration of glycopyrronium decreases in a multiphasic manner. The mean terminal T_1/2 is longer after inhalation (33-57 h) than after IV (6.2 h) or oral administration (2.8 h). The nature of the elimination suggests prolonged absorption in the lungs and/or penetration of glycopyrronium into the systemic circulation during and up to 24 hours after inhalation.

Mometasone furoate

Following IV bolus administration, the mean terminal T_1/2 of mometasone furoate is approximately 4.5 hours. According to a study using a radiolabeled isotope, after inhalation, Mometasone furoate is excreted primarily via the intestine (74%) and, to a lesser extent, in the urine (8%).

Linearity/non-linearity

After single and repeated inhalation administration of Enerzair Breezhaler^® 150 mcg+50 mcg+80 mcg and 150 mcg+50 mcg+160 mcg to healthy volunteers, the systemic exposure of mometasone furoate (C_max and AUC_0-24h) increased proportionally with the dose. In patients with bronchial asthma following administration of doses 150 mcg+50 mcg+80 mcg and 150 mcg+50 mcg+160 mcg, a less than proportional increase (1.7-fold) in the systemic exposure of mometasone furoate at steady state was observed. An assessment of dose-dependent increases in exposure for indacaterol or glycopyrronium was not performed, as only one dosage of each was used in the Enerzair Breezhaler^® preparation.

Pharmacokinetics in special patient groups

Results of pharmacokinetic analysis in patients with bronchial asthma following inhalation administration of Enerzair Breezhaler^® indicated no significant influence of age, sex, body weight, smoking status, baseline estimated glomerular filtration rate (eGFR), or baseline FEV₁ on the systemic exposure of indacaterol, glycopyrronium, or mometasone furoate.

The safety and efficacy of Enerzair Breezhaler^® in patients under 18 years of age have not been established.

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of indacaterol, glycopyrronium, and mometasone furoate following administration of Enerzair Breezhaler^® has not been studied. However, studies evaluating the properties of each individual component have been conducted.

Indacaterol: In patients with mild or moderate hepatic impairment, no significant changes in the C_max or AUC of indacaterol were observed. Furthermore, no differences in plasma protein binding were noted between patients with mild or moderate hepatic impairment and healthy volunteers. Studies in patients with severe hepatic impairment have not been conducted.

Glycopyrronium: Clinical studies in patients with hepatic impairment have not been conducted. Glycopyrronium is eliminated from the systemic circulation primarily by the kidneys. It is assumed that impaired hepatic metabolism of glycopyrronium will not lead to a clinically significant increase in exposure.

Mometasone furoate: Results from a study evaluating the single-dose administration of an inhaled form of mometasone furoate at a dose of 400 mcg in patients with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment indicate that detectable peak plasma concentrations of mometasone furoate were observed in only one or two patients in each treatment group (50-105 pg/mL). The frequency of detectable peak plasma concentrations appears to increase with the severity of hepatic impairment; however, such peak concentrations (the lower limit of quantification was 50 pg/mL) were recorded only in a few cases.

Patients with renal impairment

An assessment of the effect of renal impairment on the pharmacokinetics of indacaterol, glycopyrronium, and mometasone furoate in clinical studies of the drug has not been conducted. In a population pharmacokinetic analysis, eGFR was not a statistically significant predictor for the systemic exposure of indacaterol, glycopyrronium, and mometasone furoate following administration of Enerzair Breezhaler^® in patients with bronchial asthma.

Since urinary excretion does not significantly influence the overall elimination of indacaterol and mometasone furoate, the effect of renal impairment on the systemic exposure of these substances has not been studied.

Renal impairment affects the systemic exposure of glycopyrronium when used in monotherapy. A moderate increase in total systemic exposure of up to 1.4-fold was observed in patients with mild and moderate renal impairment and up to 2.2-fold in patients with severe renal impairment and end-stage chronic kidney disease (CKD). According to population pharmacokinetic analysis data, in patients with bronchial asthma and an absolute GFR of 58 or 143 mL/min, the AUC_0-24h of glycopyrronium increased by 27% or 19%, respectively, compared to patients with a GFR of 93 mL/min.

According to population pharmacokinetic analysis data in patients with COPD and concomitant mild to moderate renal impairment (GFR ≥ 30 mL/min/1.73 m²), glycopyrronium can be used at the recommended doses.

Race, ethnicity, and other special patient groups

No significant differences in total systemic exposure (by AUC) of indacaterol, glycopyrronium, or mometasone furoate were found between patients of Japanese origin and Caucasians. Currently, there is insufficient pharmacokinetic data for patients of other ethnicities or races.

In patients with bronchial asthma, the total systemic exposure of glycopyrronium (AUC) may increase by 1.8-fold and 2.5-fold with low body weight and with low body weight (35 kg) combined with low absolute GFR (45 mL/min), respectively.

Indications

• Maintenance therapy of bronchial asthma in adult patients in whom adequate disease control has not been achieved with a combination of a long-acting beta₂-adrenergic agonist and a medium or high dose of an inhaled glucocorticosteroid, including those who have experienced one or more exacerbations of bronchial asthma in the previous year.

ICD codes

Dosage Regimen

For inhalation use only.

The drug is a powder for inhalation in capsules, which should be used only for inhalation through the mouth using a special inhalation device (Breezhaler^®) included in the package. A new inhalation device should be used with each new package. The capsules must not be taken orally. The powder for inhalation capsules should be stored in the blister protected from light and moisture and removed from it immediately before use. After inhalation, rinse the mouth with water without swallowing.

The drug is inhaled once daily at the same time each day. If a dose is missed, it should be taken as soon as possible. The patient should be informed not to use more than 1 dose per day.

Before starting treatment with the drug, the patient should be instructed in the correct technique for using the inhalation device.

If there is no improvement in respiratory function, it should be verified that the patient is using the drug correctly. The drug should be inhaled, not swallowed.

Special patient groups

Patients over 65 years of age

No dose adjustment of the drug is required in patients aged ≥65 years.

Children

The safety and efficacy of Enerzair Breezhaler^® in children under 18 years of age have not been established.

Use in patients with renal impairment

No dose adjustment is required when using the drug in patients with mild or moderate renal impairment. Caution should be exercised in patients with severe renal impairment or end-stage CKD requiring dialysis. Enerzair Breezhaler^® should be used only in cases where the expected benefit outweighs the potential risk.

Use in patients with hepatic impairment

No dose adjustment is required when using the drug in patients with mild and moderate hepatic impairment. The use of the drug in patients with severe hepatic impairment has not been studied; therefore, in this subgroup of patients, Enerzair Breezhaler^® should be used only in cases where the expected benefit outweighs the potential risk.

Instructions for use of the Breezhaler^® inhalation device

The package of the medicinal product Enerzair Breezhaler^® contains

• 1 inhalation device – Breezhaler^®;
• 1 or more blisters with powder for inhalation capsules.

This section provides instructions for using the inhalation device, as well as for its care. Before using the Breezhaler^® device, carefully read the instructions and follow the recommendations provided.

If you have additional questions, it is recommended to consult a healthcare professional.

Before using the device, read the instructions below in full.

1. Insert the capsule

Step 1a

Remove the cap.

Step 1b

Open the Breezhaler.

Step 1c

Remove the capsule from the blister.

Separate one capsule cell from the blister pack. Remove the cover foil from the blister and take out the capsule.

Do not press on the blister to remove the capsule.

Do not swallow the capsule.

Step 1d

Insert the capsule.

Do not place the capsule directly into the mouthpiece.

Step 1e

Close the Breezhaler.

2. Pierce the capsule and release

Step 2a

Pierce the capsule once.

Hold the inhalation device upright. Pierce the capsule by pressing both side buttons simultaneously. A click should be heard when the capsule is pierced. Do not pierce the capsule more than once.

Step 2b

Release the side buttons.

3. Inhale deeply

Step 3a

Exhale fully.

Do not blow into the inhalation device.

Step 3b

Inhale the medicine deeply.

Hold the inhalation device as shown in the picture. Place the mouthpiece of the device in your mouth and close your lips tightly around it.

Do not press the side buttons.

Take a rapid and as deep an inhalation as possible.

A rattling sound will be heard during inhalation.

The patient may taste the medicine during inhalation.

Step 3c

Hold your breath.

Hold your breath for no more than 5 seconds.

Step 3d

After each use, rinse your mouth with water without swallowing.

4. Check that the capsule is empty

Open the inhalation device and check that no powder remains in the capsule.

If powder remains in the capsule, you should

• Close the inhaler;
• Repeat steps 3a-3d.

Disposal of the empty capsule

The empty capsule can be disposed of with household waste.

Close the inhalation device and put the cap on it.

Important information

Enerzair Breezhaler^® capsules must be stored in the blister pack and removed immediately before use.

When removing the capsule from the blister, do not push it through the foil.

Do not swallow the capsule.

Do not use Enerzair Breezhaler^® capsules with other inhalation devices.

Do not use the Breezhaler^® inhalation device with other medicines.

Do not place capsules in your mouth or the mouthpiece of the inhalation device.

Do not press the side buttons more than once.

Do not blow into the mouthpiece.

Do not press the side buttons while inhaling through the mouthpiece.

Handle capsules only with dry hands.

Do not wash the inhaler with water.

Cleaning the inhalation device

Wipe the inside and outside of the mouthpiece with a clean, dry, lint-free cloth to remove any powder residue. Keep the inhaler dry. Do not wash the inhaler with water.

Disposal of the inhaler after use

After using all capsules, the inhalation device must be disposed of. Information on methods for disposing of the medicine and the inhaler can be obtained from your pharmacist.

Adverse Reactions

The safety profile of Enerzair Breezhaler^® was studied in Phase III trials: 1233 adult patients with bronchial asthma who received therapy with Enerzair Breezhaler^® at doses of 150 mcg+50 mcg+80 mcg or 150 mcg+50 mcg+160 mcg once daily for 52 weeks.

The most frequent adverse reactions associated with the use of Enerzair Breezhaler^® were asthma (exacerbation), nasopharyngitis, upper respiratory tract infection, and headache.

Adverse reactions (ARs) are grouped according to the MedDRA classification by system organ class. Within each system organ class, ARs are listed in order of decreasing frequency. The following criteria were used to assess frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated reports. Within each frequency group, ARs are presented in order of decreasing severity.

¹Oral candidiasis, oropharyngeal candidiasis.

²Asymptomatic bacteriuria, bacteriuria, cystitis, urethritis, genitourinary tract infections, viral urinary tract infections.

³Drug eruption, drug hypersensitivity, sensitization, rash, pruritic rash, urticaria.

⁴Blood glucose increased, hyperkalemia.

⁵Tension headache.

⁶Sinus tachycardia, supraventricular tachycardia, tachycardia.

⁷Dysphagia, oropharyngeal discomfort, oropharyngeal pain, throat irritation.

⁸Chronic gastritis, enteritis, gastritis, gastroenteritis, gastrointestinal inflammation.

⁹Dry mouth, dry throat.

¹⁰Drug eruption, rash, papular rash, pruritic rash.

¹¹Eye pruritus, skin pruritus, genital pruritus.

¹²Back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain.

If any of the side effects mentioned in the instructions get worse, or if the patient notices any other side effects not listed in the instructions, they should inform their doctor.

Contraindications

• Hypersensitivity to glycopyrronium, indacaterol, mometasone furoate, or any other components of the drug;
• Age under 18 years (efficacy and safety have not been established);
• Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption (the drug contains lactose);
• Concomitant use with medicinal products containing other long-acting beta₂-adrenergic agonists or long-acting anticholinergics.

With caution

• Concomitant cardiovascular diseases (coronary artery disease, acute myocardial infarction, arterial hypertension, cardiac arrhythmias, QT_c interval prolongation);
• Convulsive disorders;
• Thyrotoxicosis;
• Diabetes mellitus;
• Congenital long QT syndrome;
• Concomitant use of medicines that prolong the QT interval (class IA and III antiarrhythmic drugs, tricyclic and tetracyclic antidepressants, antipsychotics, macrolides, antifungal agents, imidazole derivatives, some antihistamines, including astemizole, terfenadine, ebastine);
• In case of hyperreactivity to the action of beta₂-adrenergic agonists;
• Narrow-angle glaucoma;
• Severe hepatic impairment (use of the drug is possible only if the expected benefit outweighs the potential risk);
• Conditions accompanied by urinary retention;
• Severe renal impairment (GFR below 30 mL/min/1.73 m²), including end-stage CKD requiring hemodialysis (use of the drug is possible only if the expected benefit outweighs the potential risk);
• Pulmonary tuberculosis;
• Chronic or untreated infections;
• Confirmed or suspected QT interval prolongation or patients who are taking drugs that affect the QT interval should use long-acting beta₂-agonists (LABA) or combination drugs containing LABA with caution;
• Concomitant use with general anesthetics from the barbiturate group.

Use in Pregnancy and Lactation

Summary of risks

Currently available data on the use of Enerzair Breezhaler^® (or its individual components: indacaterol, glycopyrronium, and Mometasone furoate) in pregnant women are insufficient to draw any conclusions regarding the risks associated with the use of the drug.

Indacaterol and glycopyrronium did not show teratogenic effects in rats and rabbits after subcutaneous or inhalation administration, respectively. In reproductive toxicity studies, administration of mometasone furoate to pregnant female mice, rats, and rabbits led to an increased incidence of fetal malformations and decreased fetal survival and growth.

The drug Enerzair Breezhaler^® should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Risk to maternal, embryo and/or fetal health associated with the disease

In the absence of control or with insufficient control of maternal bronchial asthma, the risk of developing some negative perinatal outcomes, such as preeclampsia, premature birth, low newborn weight, or small fetal size for gestational age, increases.

Patients with bronchial asthma should be carefully monitored during pregnancy; if necessary, the drug dose may be adjusted to maintain optimal disease control.

Labor and delivery

Indacaterol

Like other drugs containing beta₂-adrenergic agonists, indacaterol may inhibit labor due to its relaxing effect on uterine smooth muscle.

Glycopyrronium

In pregnant women who underwent a caesarean section, 86 minutes after a single intramuscular injection of glycopyrronium bromide at a dose of 0.006 mg/kg, the plasma concentration of glycopyrronium in venous (0.28 (0.25) ng/ml) and arterial umbilical cord (0.18 (0.11) ng/ml) blood was low (clinically insignificant).

Breastfeeding period

There is no information on the penetration of indacaterol, glycopyrronium, or mometasone into human breast milk, their effect on breast milk production, or their effect on the breastfed child. Other inhaled corticosteroids similar to mometasone furoate penetrate into human breast milk.

When deciding to discontinue breastfeeding or to discontinue/temporarily interrupt therapy with the drug, the benefit of breastfeeding for the child and the benefit of therapy for the mother should be taken into account.

Fertility

Results from reproductive function studies and other data from animal studies indicate an absence of problems in men or women related to fertility.

Use in Hepatic Impairment

No dose adjustment is required when using the drug in patients with mild to moderate hepatic impairment. The use of the drug in patients with severe hepatic impairment has not been studied; therefore, in this subgroup of patients, the drug Enerzair Breezhaler^® should be used only if the expected benefit outweighs the potential risk.

Use in Renal Impairment

No dose adjustment is required when using the drug in patients with mild or moderate renal impairment. Caution should be exercised in patients with severe renal impairment or end-stage CKD requiring dialysis.

Pediatric Use

The safety and efficacy of the drug Enerzair Breezhaler^® in children under 18 years of age have not been established; its use is contraindicated.

Geriatric Use

No dose adjustment of the drug is required in patients aged ≥65 years.

Special Precautions

Worsening of disease

The drug Enerzair Breezhaler^® should not be used to relieve acute symptoms of bronchial asthma, including acute episodes of bronchospasm, for which the use of short-acting bronchodilators is required. An increased frequency of use of short-acting bronchodilators to relieve symptoms indicates a loss of disease control and the need for the patient to be examined by a doctor. Without medical supervision, the patient should not discontinue treatment with the drug, as symptoms may recur upon discontinuation of therapy.

When using the drug Enerzair Breezhaler^®, symptoms of bronchial asthma may develop, as well as exacerbations of the disease.

Abrupt discontinuation of therapy with the drug is not recommended. If the therapy is considered ineffective by the patient, it is necessary to continue using the drug and consult a doctor. An increased frequency of use of short-acting bronchodilators (“rescue therapy”) indicates a worsening of the disease and requires a review of treatment. Sudden, progressive worsening of bronchial asthma can be life-threatening, and therefore the patient requires urgent medical examination.

Hypersensitivity reactions

Cases of immediate-type hypersensitivity reactions have been observed with the use of the drug Enerzair Breezhaler^®. If signs indicating the development of an allergic reaction appear, especially angioedema (including difficulty breathing or swallowing, swelling of the tongue, lips, and face), urticaria, or skin rash, the use of the drug should be discontinued immediately and switched to alternative treatment.

Paradoxical bronchospasm

As with the use of other drugs for inhalation use, therapy with the drug Enerzair Breezhaler^® may lead to the development of life-threatening paradoxical bronchospasm. If paradoxical bronchospasm develops, the use of the drug Enerzair Breezhaler^® should be discontinued immediately and switched to alternative treatment.

Effect of beta₂-adrenergic agonists on the cardiovascular system

Like other drugs containing beta₂-adrenergic agonists, the drug Enerzair Breezhaler^® may have a clinically significant effect on the cardiovascular system, manifested as increased blood pressure, increased heart rate, and/or the occurrence of corresponding symptoms. If such effects develop, discontinuation of therapy may be required.

The drug Enerzair Breezhaler^® should be used with caution in patients with cardiovascular diseases (coronary artery disease, acute myocardial infarction, cardiac arrhythmia, arterial hypertension), convulsive disorders, or thyrotoxicosis, as well as in patients with hypersensitivity to beta₂-adrenergic receptor agonists.

In the clinical development program for indacaterol/glycopyrronium/mometasone furoate, patients with unstable coronary artery disease, a history of myocardial infarction within the last 12 months, left ventricular failure of New York Heart Association (NYHA) class III/IV, arrhythmia, uncontrolled arterial hypertension, cerebrovascular diseases, a history of long QT syndrome, as well as patients receiving treatment with drugs known to prolong the QT_c interval were excluded from the studies. Thus, there are no safety data for patients in the above categories.

Furthermore, the following electrocardiographic changes may be observed with the use of beta₂-adrenergic agonists: T-wave flattening, QT interval prolongation, and ST-segment depression (however, the clinical significance of these changes has not been established). Thus, in patients with confirmed or suspected QT interval prolongation or in patients receiving drugs that affect the QT interval, long-acting beta₂-agonists (LABA) or combination drugs containing LABA, including the drug Enerzair Breezhaler^®, should be used with caution.

Hypokalemia with the use of beta-adrenergic agonists

In some patients, the use of beta₂-adrenergic agonists may cause significant hypokalemia, leading to the development of adverse reactions from the cardiovascular system. The decrease in serum potassium is usually transient and does not require correction. In patients with severe bronchial asthma, hypokalemia may be caused by hypoxia and concomitant therapy, which in turn may increase the predisposition to develop cardiac arrhythmia. In clinical studies, no clinically significant effects of hypokalemia were observed when the drug was used at recommended therapeutic doses.

Hyperglycemia

Inhalation of high doses of beta₂-adrenergic agonists with corticosteroids may increase plasma glucose concentration. When initiating therapy with the drug in patients with diabetes mellitus, plasma glucose concentration should be monitored more carefully.

The use of the drug Enerzair Breezhaler^® in patients with type I diabetes mellitus or uncontrolled type II diabetes mellitus has not been studied.

Cholinergic action of glycopyrronium

Like other anticholinergic drugs, Enerzair Breezhaler^® should be used with caution in patients with narrow-angle glaucoma or urinary retention. The patient should be informed about the signs and symptoms of an acute attack of narrow-angle glaucoma and the need to discontinue the use of the drug and immediately consult a doctor if the corresponding signs and symptoms occur.

Patients with severe renal impairment

Caution should be exercised in patients with severe renal impairment (GFR <30 ml/min/1.73 m²), including patients with end-stage CKD requiring dialysis. The drug Enerzair Breezhaler^® should be used only if the expected benefit outweighs the potential risk.

Prevention of oral and pharyngeal infections

To reduce the risk of oropharyngeal candidiasis infection, patients should be advised to rinse their mouth or gargle with water without swallowing it, or to brush their teeth after inhaling the prescribed dose.

Systemic effects of glucocorticosteroids

Systemic effects may develop with the use of inhaled corticosteroids, especially when used in high doses and for a prolonged period of time. These phenomena occur less frequently than with the use of oral corticosteroids, and they may also vary depending on individual patient characteristics and the corticosteroids used.

The drug Enerzair Breezhaler^® should be used with caution in patients with pulmonary tuberculosis or a chronic or untreated infection.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take Enerzair Breezhaler^®.

Effect on ability to drive vehicles and machinery

The drug Enerzair Breezhaler^® has no or negligible influence on the ability to drive vehicles and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

The maximum recommended dose of the drug Enerzair Breezhaler^® is 50 mcg+150 mcg+160 mcg once daily. Limited data on overdose with the drug Enerzair Breezhaler^® were obtained in clinical studies.

Symptoms of overdose may develop signs, symptoms, or side effects associated with the pharmacological action of individual components (e.g., tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmia, metabolic acidosis, hypokalemia, hyperglycemia, increased intraocular pressure (accompanied by eye pain, visual impairment, or eye redness), constipation, difficulty urinating, suppression of the hypothalamic-pituitary-adrenal system).

Treatment in case of suspected overdose, general supportive and symptomatic therapy should be initiated. To treat the side effects of beta₂-adrenergic agonists, the use of cardioselective beta-blockers can be considered, exclusively under medical supervision and with extreme caution, since the use of beta₂-blockers can provoke the development of bronchospasm. In severe cases, hospitalization may be required.

Drug Interactions

Studies of the interaction of the drug Enerzair Breezhaler^® with other drugs have not been conducted. Information on possible drug interactions of the drug Enerzair Breezhaler^® is based on data on possible drug interactions when using each of the active substances separately. When the drug Enerzair Breezhaler^® is used by inhalation at clinical (therapeutic) doses simultaneously with other drugs, the development of clinically significant drug interactions mediated by this drug is unlikely due to low plasma concentrations.

Concurrent inhalation use of indacaterol, glycopyrronium, and mometasone furoate does not affect the pharmacokinetics of any of the active substances at steady state in serum.

Drugs that prolong the QT_c interval

As with the use of other beta₂-adrenergic agonists, caution should be exercised when using the drug Enerzair Breezhaler^® in patients taking MAO inhibitors, tricyclic antidepressants, or other drugs capable of prolonging the QT interval, due to the possibility of enhancing the effect of these drugs on the QT interval length. Drugs capable of prolonging the QT interval may increase the risk of ventricular arrhythmia.

Drugs that can cause hypokalemia

Concomitant use with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may enhance the potential hypokalemic effect of beta₂-adrenergic agonists (see the “Special Precautions” section).

Beta-blockers

Beta-blockers may weaken the effect or prevent the action of beta₂-adrenergic agonists. Therefore, the drug Enerzair Breezhaler^® is not recommended to be used concomitantly with beta-blockers unless there are compelling reasons for their combined use. If concomitant use of both classes of drugs is necessary, cardioselective beta-blockers should be preferred (while exercising caution).

Interaction with CYP3A4 and P-glycoprotein inhibitors

Inhibition of CYP3A4 and P-glycoprotein (Pgp) does not affect the safety of using the drug Enerzair Breezhaler^® at therapeutic doses.

Inhibition of the main enzymes contributing to the clearance of indacaterol (CYP3A4 and Pgp) or mometasone furoate (CYP3A4) increases the systemic exposure of indacaterol or mometasone furoate by 2 times.

According to the experience of use in clinical studies at a dose of 600 mcg for up to one year, the degree of increase in indacaterol exposure as a result of drug interactions does not raise safety concerns.

Since very low plasma concentrations are achieved after inhalation, clinically significant drug interactions with mometasone furoate appear unlikely. However, when used concomitantly with potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole, nelfinavir, ritonavir, cobicistat), an increase in the systemic exposure of mometasone furoate is possible.

Cimetidine or other inhibitors of organic cation transport

In clinical studies in healthy volunteers, cimetidine, an inhibitor of organic cation transport affecting the renal clearance of glycopyrronium, increased the total exposure of glycopyrronium by 22% (AUC) and decreased renal clearance by 23%. Given the magnitude of these changes, no clinically significant drug interaction is expected with the concomitant use of glycopyrronium with cimetidine or other inhibitors of organic cation transport.

Other long-acting anticholinergic drugs and long-acting beta₂-adrenergic agonists

Concomitant use of the drug Enerzair Breezhaler^® with other medicinal products containing long-acting anticholinergic drugs or long-acting beta₂-adrenergic agonists has not been studied and is not recommended due to the possible development of adverse reactions.

Storage Conditions

The drug should be stored in the original packaging (in the carton), protected from light, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 36 months. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.