Ultibro^® Breezhaler (Capsules) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Pharma Stein AG (Switzerland)

Packaging and Quality Control Release

NOVARTIS PHARMA STEIN, AG (Switzerland)

Or

NOVARTIS NEVA, LLC (Russia)

ATC Code

R03AL04 (Indacaterol and glycopyrronium bromide)

Active Substances

Indacaterol (Rec.INN registered by WHO)

Glycopyrronium bromide (Rec.INN registered by WHO)

Dosage Form

Ultibro® Breezhaler®

Powder for inhalation capsules 50 mcg+100 mcg: 6, 12, 30, 48, 90, or 150 pcs. in a kit with an inhalation device (breezhaler)

Dosage Form, Packaging, and Composition

Powder for inhalation capsules hard, size No. 3, transparent, colorless, with black marking on the cap and the inscription “IGP110.50” in blue ink under a double blue band on the body; capsule contents – white or almost white powder.

Excipients : lactose monohydrate – 24.757 mg, magnesium stearate – 37 mcg.

Capsule shell composition: hypromellose – 45.7 mg, water – 2.7 mg, carrageenan – 420 mcg, potassium chloride – 180 mcg.
Black ink composition: shellac, black iron oxide dye (E172), propylene glycol, potassium hydroxide, water.
Blue ink composition: shellac, indigo carmine (E132), propylene glycol, titanium dioxide.

6 pcs. – blisters made of PA/Al/PVC and aluminum foil (1) in a kit with an inhalation device (breezhaler) – cardboard packs.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (2) in a kit with an inhalation device (breezhaler) – cardboard packs.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (5) in a kit with an inhalation device (breezhaler) – cardboard packs.

Multipack.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (1) – cardboard packs (25) in a kit with an inhalation device (breezhaler) – boxes.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (2) – cardboard packs (4) in a kit with an inhalation device (breezhaler) – boxes.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (5) – cardboard packs (3) in a kit with an inhalation device (breezhaler) – boxes.

Clinical-Pharmacological Group

Combined bronchodilator drug – m-cholinoreceptor blocker + beta₂-adrenomimetic

Pharmacotherapeutic Group

Combined bronchodilator agent (m-cholinergic blocker + selective beta2-adrenomimetic)

Pharmacological Action

Combined inhalation drug.

Glycopyrronium and indacaterol cause relaxation of bronchial smooth muscle, mutually enhancing the bronchodilatory effect of each other due to different mechanisms of action directed at different types of receptors. Since the density of m-cholinergic receptors and β₂-adrenergic receptors in the central and peripheral airways differs, beta₂-adrenomimetics are more effective for bronchodilation of the peripheral airways, while m-cholinergic blockers have a more pronounced effect on the central airways. Thus, the combination of an m-cholinergic blocker and a beta₂-adrenomimetic promotes optimal bronchodilation throughout the entire lower human airways.

Glycopyrronium is a long-acting inhaled m-cholinergic blocker intended for maintenance therapy of bronchial obstruction disorders in patients with COPD. Nervous regulation of bronchoconstriction is provided by the parasympathetic nervous system, thus, cholinergic stimulation is a key component of reversible bronchial obstruction in COPD. The mechanism of action of glycopyrronium is based on blocking the bronchoconstrictive 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 subtypes m_1-3 are involved in the physiological function of the respiratory system. Glycopyrronium has 4-5 times greater selectivity for m₁ and m₃ receptors compared to m₂ receptors. This leads to rapid onset of therapeutic effect after inhalation, which has been confirmed in clinical studies. The bronchodilatory effect of glycopyrronium after inhalation lasts more than 24 hours. The duration of its action after inhalation is due to the prolonged maintenance of therapeutic drug concentration in the lungs, as confirmed by a longer T_1/2 of the drug after inhalation compared to IV administration.

Indacaterol is a selective ultra-long-acting beta₂-adrenomimetic (for 24 hours with single use). The pharmacological action of beta₂-adrenomimetics, including indacaterol, is associated with stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cyclic 3′,5′-AMP (cAMP). Increased cAMP content leads to relaxation of bronchial smooth muscle. Indacaterol is an almost full agonist of β₂-adrenergic receptors; the stimulating effect of the drug on β₂-adrenergic receptors is 24 times stronger than on β₁-adrenergic receptors and 20 times stronger than on β₃-adrenergic receptors. After inhalation, indacaterol provides rapid and prolonged bronchodilation. The selectivity of indacaterol is similar to that of formoterol. After inhalation, indacaterol exerts a local bronchodilatory effect. In isolated human bronchi, indacaterol has a rapid and long-lasting effect.

Pharmacokinetics

After inhalation of the drug containing this combination, the mean time to reach C_max of glycopyrronium bromide and indacaterol in plasma was 15 min and 5 min, respectively.

After inhalation, glycopyrronium is rapidly absorbed and reaches C_max in plasma within 5 min. Approximately 90% of the systemic exposure of glycopyrronium is due to absorption in the lungs, and 10% to absorption in the gastrointestinal tract. The absolute bioavailability of glycopyrronium after inhalation is estimated at 40% of the delivered dose. With regular inhalations (once daily), C_ss of glycopyrronium bromide is reached within 1 week. The exposure of glycopyrronium at steady state was 1.4-1.7 times higher than after the first inhalation. The C_max of glycopyrronium at steady state (when inhaled at the recommended dose once daily) and the plasma concentration of glycopyrronium immediately before the next dose are 166 pg/ml and 8 pg/ml, respectively. After IV administration, V_ss was 83 L and V_z was 376 L. The apparent volume of distribution in the terminal phase after inhalation (V_z/F) was 7310 L, reflecting its slower elimination after inhalation. In vitro binding of glycopyrronium to human plasma proteins is 38-41% at concentrations of 1-10 ng/ml. These concentrations are at least 6 times higher than the C_max at steady state when used at a dose of 50 mcg once daily. In vitro, hydroxylation of glycopyrronium was noted to form various mono- and bis-hydroxylated 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. 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 IV administration, it is assumed that M9 is formed from the fraction of the active substance that entered via the gastrointestinal tract after inhalation through presystemic hydrolysis and/or during the “first pass” through the liver. After inhalation or IV administration, only minimal amounts of M9 were detected in urine (≤0.5% of the administered dose). Glucuronic and/or sulfate conjugates of glycopyrronium were detected in human urine after repeated inhalations in amounts of approximately 3% of the delivered dose. Renal excretion of glycopyrronium reaches 60-70% of total plasma clearance, 30-40% is excreted by other routes – with bile or due to metabolism. In healthy volunteers and COPD patients receiving glycopyrronium at doses from 50 to 200 mcg once daily, single and multiple, the mean renal clearance of glycopyrronium ranged from 17.4 to 24.4 L/h. Renal excretion of glycopyrronium is due to active tubular secretion. Up to 23% of the dose is found unchanged in urine. The plasma concentration of glycopyrronium bromide 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 elimination pattern suggests prolonged absorption in the lungs and/or penetration of glycopyrronium into the systemic circulation during and after 24 hours after inhalation. In COPD patients, systemic exposure and renal excretion of glycopyrronium at steady state increased proportionally with dose in the range from 50 mcg to 200 mcg.

Indacaterol. The mean time to reach C_max of indacaterol in serum is about 15 min after single or repeated inhalations. The serum concentration of indacaterol increases with repeated use of the drug once daily. C_ss of the substance in blood is reached within 12-15 days of drug use. When the drug is inhaled at doses from 60 to 480 mcg (dose delivered to the lungs) with a frequency of once daily for 14 days, the accumulation factor of indacaterol, estimated by the AUC value of the drug on days 1 and 14 or 15, ranges from 2.9 to 3.8. After IV administration, the volume of distribution in the terminal phase (V_z) of indacaterol was 2361-2557 L, indicating significant distribution of the drug. Binding to human plasma proteins in vitro is approximately 95%. When orally administered radiolabeled indacaterol, unchanged indacaterol is the main component in serum and accounts for approximately 1/3 of the daily AUC of the drug. Among the metabolites of indacaterol in serum, the hydroxylated derivative of indacaterol is the most determined. Indacaterol phenolic O-glucuronide and hydroxylated indacaterol are found in smaller amounts. In addition, diastereomers of the hydroxylated derivative, N-glucuronide of indacaterol, and C- and N-dealkylation products are detected. The UGT1A1 isoenzyme is the only isoenzyme that metabolizes indacaterol to phenolic O-glucuronide. Hydroxylation of indacaterol occurs mainly with the help of the CYP3A4 isoenzyme. It has also been established that indacaterol is a low-affinity substrate for the membrane transporter molecule P-glycoprotein (Pgp). The amount of unchanged indacaterol excreted by the kidneys is less than 2.5% of the delivered dose. The renal clearance of indacaterol averaged 0.46-1.2 L/h. Given that the serum clearance of indacaterol is 18.8-23.3 L/h, it is obvious that its renal excretion is insignificant (approximately 2-5% of systemic clearance). When taken orally, indacaterol was excreted mainly through the intestine: unchanged (54% of the dose) and as hydroxylated metabolites (23% of the dose). The serum concentration of indacaterol decreases in a multiphasic manner with a mean terminal T_1/2 in the range of 45.5 to 126 h. The effective T_1/2, calculated based on the accumulation of indacaterol after repeated use, varied from 40 to 52 h, which is consistent with the established time to reach steady state (12-15 days). The AUC of indacaterol at steady state increased proportionally to the delivered dose in the range from 120 to 480 mcg. The systemic exposure of indacaterol increases proportionally with increasing dose (from 150 to 600 mcg). The systemic exposure of the drug is due to its absorption in both the lungs and the gastrointestinal tract.

Indications

Long-term maintenance therapy of bronchial obstruction disorders in patients with chronic obstructive pulmonary disease, relieving symptoms and reducing the number of exacerbations.

ICD codes

Dosage Regimen

Use Ultibro^® Breezhaler^® by inhalation once daily only.

Inhale the contents of one capsule each day, at the same time every day.

Do not use the inhaler more than once in a 24-hour period.

This regimen is for maintenance therapy and is not for relieving acute bronchospasm attacks.

Ensure proper inhalation technique is followed for effective drug delivery to the lungs.

If a dose is missed, take it as soon as remembered on the same day; do not double the next dose.

Adverse Reactions

Infections and parasitic diseases very common – upper respiratory tract infection; common – nasopharyngitis, urinary tract infection, sinusitis, rhinitis.

Immune system disorders common – hypersensitivity. During post-registration studies – angioedema.

Metabolism and nutrition disorders common – hyperglycemia and diabetes mellitus.

Psychiatric disorders uncommon – insomnia.

Nervous system disorders common – dizziness, headache; rare – paresthesia.

Eye disorders uncommon – glaucoma.

Cardiac disorders uncommon – coronary artery disease, atrial fibrillation, tachycardia, palpitations.

Respiratory, thoracic and mediastinal disorders common – cough, oropharyngeal pain, throat irritation; uncommon – epistaxis.

Gastrointestinal disorders common – dyspepsia, dental caries; uncommon – dry mouth, gastroenteritis.

Skin and subcutaneous tissue disorders uncommon – skin rash/itching.

Musculoskeletal and connective tissue disorders uncommon – muscle and bone pain; muscle spasm, pain in extremity, myalgia.

Renal and urinary disorders common – bladder obstruction, urinary retention.

General disorders and administration site conditions common – fever, chest pain; uncommon – peripheral edema, fatigue. During post-registration studies – dysphonia.

Contraindications

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

Concomitant use with drugs containing other long-acting beta₂-adrenomimetics or long-acting m-cholinergic blockers is not recommended.

With caution

Concomitant cardiovascular diseases (coronary artery disease /including unstable angina/, acute myocardial infarction /including history/, arterial hypertension, cardiac arrhythmias, QT_c interval prolongation /QT corrected >0.44 s/); convulsive disorders; thyrotoxicosis; diabetes mellitus; congenital long QT syndrome; concomitant use of drugs that prolong the QT interval (class IA and III antiarrhythmic drugs, tricyclic and tetracyclic antidepressants, neuroleptics, macrolides, antifungal drugs, imidazole derivatives, some antihistamines, including astemizole, terfenadine, ebastine), general anesthetics from the barbiturate group; with hyperreactivity to the action of beta₂-adrenomimetics; narrow-angle glaucoma; severe liver dysfunction; conditions accompanied by urinary retention, severe renal impairment (GFR below 30 ml/min/1.73 m²), including end-stage renal failure requiring hemodialysis (use of the drug is possible only if the expected benefit outweighs the potential risk).

Use in Pregnancy and Lactation

Use of this combination during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

It is not known whether glycopyrronium and/or indacaterol pass into human breast milk. However, both indacaterol and glycopyrronium (including its metabolites) have been detected in the milk of lactating animals. Given this circumstance, the use of the combination in breastfeeding women is permissible only if the intended benefit to the mother outweighs the possible risk to the child.

Pediatric Use

Contraindicated in children under 18 years of age (efficacy and safety not established).

Geriatric Use

No dose adjustment of the drug is required in patients aged ≥75 years.

Special Precautions

Should not be used concomitantly with other drugs containing long-acting beta-adrenomimetics or long-acting m-cholinergic blockers.

This combination is not recommended for the relief of acute episodes of bronchospasm.

Before starting therapy in patients under 40 years of age, spirometric confirmation of the COPD diagnosis is required.

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

When using long-acting beta₂-adrenomimetics for the treatment of asthma, the risk of serious asthma-related adverse events, including death, increases.

Caution should be exercised when using in patients with narrow-angle glaucoma.

When inhaling beta₂-adrenomimetics in high doses, an increase in plasma glucose concentration is possible. When used in patients with diabetes mellitus, plasma glucose concentration should be regularly monitored.

Effect on ability to drive vehicles and operate machinery

If dizziness occurs, you should refrain from driving vehicles and engaging in potentially hazardous activities.

Drug Interactions

Cimetidine or other cation transporter inhibitors. In clinical studies in healthy volunteers, cimetidine, an inhibitor of organic cation transporters affecting the renal clearance of glycopyrronium, increased the exposure of glycopyrronium by 22% and decreased renal clearance by 23%. Based on these indicators, no clinically significant interaction is expected with the concomitant use of glycopyrronium bromide with cimetidine or other cation transporter inhibitors.

M-cholinoblockers. Concurrent use with medicinal products containing long-acting M-cholinoblockers is not recommended.

Beta-adrenoblockers. Since beta-adrenoblockers may weaken the effect or prevent the action of beta₂-adrenomimetics, this combination is not recommended for concurrent use with beta-adrenoblockers (including eye drops) in the absence of compelling reasons for their combined use. If the use of both classes of drugs is necessary, preference should be given to cardioselective beta-adrenoblockers with caution.

Drugs that prolong the QT interval. As with the use of other beta₂-adrenomimetics, caution should be exercised when using this combination in patients receiving MAO inhibitors, tricyclic antidepressants, or other drugs capable of prolonging the QT interval, due to the possibility of potentiating the effect of any of the above agents regarding the duration of the QT interval. When using drugs that can prolong the QT interval, the risk of developing ventricular arrhythmia increases.

Sympathomimetic drugs. Concurrent use of indacaterol with sympathomimetics (both as monotherapy and as part of combination therapy) may increase the risk of adverse events. Concurrent use with medicinal products containing other long-acting beta₂-adrenomimetics is not recommended.

Drugs that cause hypokalemia. Concurrent use with methylxanthine derivatives, corticosteroids, or diuretics that cause hypokalemia may enhance the possible hypokalemia caused by beta₂-adrenomimetics.

Interaction at the level of the CYP3A4 isoenzyme and the P-glycoprotein membrane transporter. The interaction of indacaterol with specific inhibitors of the CYP3A4 isoenzyme and P-glycoprotein, such as ketoconazole, erythromycin, verapamil, and ritonavir, has been studied. Concurrent use of indacaterol with verapamil led to an increase in AUC by 1.4-2 times and an increase in C_max by 1.5 times. When using indacaterol with erythromycin, an increase in AUC by 1.4-1.6 times and C_max by 1.2 times was noted. Combined inhibition of P-glycoprotein and the CYP3A4 isoenzyme when using the potent dual inhibitor ketoconazole led to an increase in AUC and C_max by 2 and 1.4 times, respectively. When using indacaterol concurrently with ritonavir (an inhibitor of the CYP3A4 isoenzyme and P-glycoprotein), an increase in AUC by 1.6-1.8 times was noted, however, C_max remained unchanged. Collectively, the data suggest that systemic clearance is influenced by variations in the activity of P-glycoprotein and the CYP3A4 isoenzyme, with the twofold increase in AUC caused by the use of the potent dual inhibitor ketoconazole reflecting the effect of maximum dual inhibition. The degree of increase in exposure due to drug interaction is not a safety concern based on the experience of using indacaterol in clinical studies lasting more than 1 year at a dose of 600 mcg (twice the maximum recommended dose).

In vitro studies have shown that at exposures achieved in clinical practice, indacaterol has a low potential for drug interaction with other drugs at the level of metabolism.

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.