ULTIBRO BREEZHALER Indacaterol Maleate / Glycopyrronium Bromide 110mcg / 50mcg Hard Capsule 1's

Information related to indacaterol/glycopyrronium (Ultibro Breezhaler): In a single dose study in healthy volunteers the 4-fold of the therapeutic dose of indacaterol/glycopyrronium (Ultibro Breezhaler) (four dose steps of 110/50 microgram separated by one hour, each) was well tolerated with no relevant effects on heart rate, QTc-interval, serum potassium or blood glucose.
In COPD patients, doses of up to 600/100 microgram were inhaled over two weeks and there were no relevant effects on heart rate, QTc-interval, blood glucose or serum potassium. There was an increase in ventricular ectopies after 14 days of dosing with 300/100 and 600/100 microgram indacaterol/glycopyrronium, but low prevalence and small patient numbers (N=49 and N=51 for 600/100 microgram and 300/100 microgram indacaterol/glycopyrronium, respectively) did preclude accurate analysis. In a total of four patients non-sustained ventricular tachycardia was recorded with the longest episode recorded being 9 beats (4 seconds).
An overdose could lead to exaggerated effects typical of beta₂-adrenergic stimulants, i.e. tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalemia, and hyperglycemia or could induce anticholinergic effects, i.e. increased intraocular pressure (causing pain, vision disturbances or reddening of the eye), obstipation or difficulties in voiding. Supportive and symptomatic treatment is indicated. In serious cases, patients should be hospitalized. Use of cardioselective beta blockers may be considered for treating beta₂-adrenergic effects, but only under the supervision of a physician and with extreme caution since the use of beta-adrenergic blockers may provoke bronchospasm.
Information related to indacaterol: In COPD patients single doses of 3000 microgram were associated with a moderate increase in pulse rate, systolic blood pressure increase and QTc interval.
Information related to glycopyrronium: In COPD patients, repeated orally inhaled administration of glycopyrronium at total doses of 100 and 200 microgram once-daily for 28 days were well tolerated.
Acute intoxication by inadvertent oral ingestion of glycopyrronium capsules is unlikely due to the low oral bioavailability (about 5%).
Peak plasma levels and total systemic exposure following i.v. administration of 150 microgram glycopyrronium bromide (equivalent to 120 microgram glycopyrronium) in healthy volunteers were respectively about 50-fold and 6-fold higher than the peak and total systemic exposure at steady-state achieved with the recommended dose (50 microgram once-daily) of glycopyrronium and were well tolerated.

 

Pregnancy: Risk Summary: There are no adequate and well-controlled studies n pregnant women to inform a product-associated risk. Likewise there are no data from the use of either indacaterol or glycopyrronium in pregnant women.
No effects on the embryo or fetus were seen at any dose level of indacaterol/glycopyrronium (Ultibro Breezhaler) during an inhalation embryo-fetal development study in rats. Indacaterol and glycopyrronium were not teratogenic in rats or rabbits following subcutaneous and inhalation administration respectively.
The potential risk for humans is unknown. Therefore as there is no adequate experience in pregnant women, it should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.
Clinical Considerations: Labor and delivery: Information related to indacaterol: Like other beta₂-adrenergic agonist containing drugs, Indacaterol may inhibit labor due to a relaxant effect on uterine smooth muscle.
Information related to glycopyrronium: In pregnant women undergoing Caesarean section, 86 minutes after a single intramuscular injection of 0.006 mg/kg glycopyrronium bromide, the concentration of glycopyrronium in the umbilical venous (0.28 (0.25) ng/mL) and in the umbilical arterial (0.18 (0.11) ng/mL) plasma were low (clinically insignificant).
Data: Animal data: Indacaterol: Adverse effects with respect to pregnancy and embryonal/foetal development in rabbits after subcutaneous administration, was only be demonstrated at doses more than 500-fold than achieved following the daily inhalation of 150 microgram in humans (based on AUC0-24h).
Glycopyrronium: Glycopyrronium was not teratogenic in rats or rabbits following inhalation. Reproduction studies in rats and other data in animals did not indicate a concern regarding pre- and post-natal development. Glycopyrronium and its metabolites did not significantly cross the placental barrier of pregnant mice, rabbits and dogs. Published data for glycopyrronium in animals do not indicate any reproductive toxicity issues.
Lactation: It is not known whether indacaterol and/or glycopyrronium passes into human breast milk. There are no data on the effects of indacaterol and/or glycopyrronium on the breastfed child or on milk production. Indacaterol and glycopyrronium (including its metabolites) have been detected in the milk of lactating rats after subcutaneous and intravenous administration. Glycopyrronium reached up to 10-fold higher concentrations in the milk than in the blood of the dam after intravenous administration. Therefore the use of indacaterol/glycopyrronium (Ultibro Breezhaler) by breastfeeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant.
Females and males of reproductive potential: There are no special recommendations.
Infertility: Information related to indacaterol and glycopyrronium: Reproduction studies or other data in animals did not indicate a concern regarding fertility in either males or females.

 

Incompatibilities: Not applicable.
Instructions for Use and Handling: Please read the full Instructions for Use before using the indacaterol/glycopyrronium (Ultibro Breezhaler).
Insert: Step 1a: Pull off cap.
Step 1b: Open inhaler.
Step 1c: Remove capsule.
Separate one of the blisters from the blister card.
Peel open the blister and remove the capsule.
Do not push the capsule through the foil.
Do not swallow capsule.
Step 1d: Insert capsule.
Never place a capsule directly into the mouthpiece.
Step 1e: Close inhaler.
Pierce and release: Step 2a: Pierce capsule once.
Hold the inhaler upright.
Pierce capsule by firmly pressing both side buttons at the same time.
The patient should hear a noise as the capsule is pierced.
Only pierce the capsule once.
Step 2b: Release side buttons.
Inhale deeply: Step 3a: Breathe out fully.
Do not blow into the inhaler.
Step 3b: Inhale medicine deeply.
Hold the inhaler.
Place the mouthpiece in the mouth and close the lips firmly around it.
Do not press the side buttons.
Breathe in quickly and as deeply as can.
During inhalation the patient will hear a whirring noise.
The patient may taste the medicine as he/she inhales.
Step 3c: Hold breath.
Hold breath for up to 5 seconds.
Check capsule is empty: Open the inhaler to see if any powder is left in the capsule.
If there is powder left in the capsule: Close the inhaler.
Repeat steps 3a to 3c.
Remove empty capsule.
Put the empty capsule in the household waste.
Close the inhaler and replace the cap.
Important Information: Ultibro Breezhaler capsules must always be stored in the blister card and only removed immediately before use.
Do not push the capsule through the foil to remove it from the blister.
Do not swallow the capsule.
Do not use the Ultibro Breezhaler capsules with any other inhaler.
Do not use the Ultibro Breezhaler inhaler to take any other capsule medicine.
Never place the capsule into the mouth or the mouthpiece of the inhaler.
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.
Do not handle capsules with wet hands.
Never wash the inhaler with water.
Cleaning the inhaler: Wipe the mouthpiece inside and outside with a clean, dry, lint-free cloth to remove any powder residue. Keep the inhaler dry. Never wash the inhaler with water.
Disposing of the inhaler after use: Each inhaler should be disposed of after all capsules have been used.
Ask the pharmacist how to dispose the medicines and inhalers that are no longer required.

 

Store at temperatures not exceeding 30°C.
Protect from moisture.

 

Pharmacology: Mechanism of action (MOA): Indacaterol/glycopyrronium (Ultibro Breezhaler): When indacaterol and glycopyrronium are administered together, they provide additive efficacy due to their different mode of action targeting different receptors and pathways to achieve small muscle relaxation. Due to the differential density of beta₂-adrenoceptors and M₃-receptors in central versus smaller airways, beta₂-agonists should be more effective in relaxing small airways whilst an anti-cholinergic compound may be more effective in large airways. Thus for optimal bronchodilation in all regions of the human lung, a combination of a beta₂-adrenergic agonist and a muscarinic antagonist may be beneficial.
Indacaterol: Indacaterol is an 'ultra' long-acting beta₂-adrenergic agonist for once-daily administration. The pharmacological effects of beta₂-adrenoceptor agonists, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta₂-receptors compared to beta₁-receptors and 20-fold greater agonist activity compared to beta₃-receptors. This selectivity profile is similar to formoterol.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a nearly full agonist at the human beta₂-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although beta₂-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta-adrenergic receptors are the predominant receptors in the human heart, there are also beta₂-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors. The precise function of beta₂-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective beta₂-adrenergic agonists may have cardiac effects.
Glycopyrronium: Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (anti-cholinergic) for once-daily maintenance bronchodilator treatment of COPD. Parasympathetic nerves are the major bronchoconstrictive neural pathway in airways, and cholinergic tone is the key reversible component of airflow obstruction in COPD. Glycopyrronium works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, thereby dilating the airways.
Of the five known muscarinic receptor subtypes (M_1-5), only subtypes M_1-3 have a defined physiological function in the human lung. Glycopyrronium bromide is a high affinity muscarinic receptor antagonist of these three receptor subtypes. It demonstrated 4- to 5-fold selectivity for the human M₃ and M₁ receptors over the human M₂ receptor in competition binding studies. It has a rapid onset of action as evidenced by observed receptor association/dissociation kinetic parameters and the onset of action after inhalation in clinical studies.
The long duration of action can be partly attributed to sustained drug concentrations in the lungs as reflected by the prolonged terminal elimination half-life of glycopyrronium after inhalation via the glycopyrronium inhaler in contrast to the half-life after i.v. administration (see Elimination as follows). Lung pharmacokinetic data in rats following inhalation of glycopyrronium bromide provides further evidence for this.
Pharmacodynamics: Primary pharmacodynamic effects: The combination of indacaterol and glycopyrronium showed a rapid onset of action within 5 minutes after dosing (see Clinical Studies, Table 1 as follows). The effect remains constant over the whole 24 h dosing interval (see Clinical Studies, Figures 1 and 2 as follows).
The mean bronchodilator effect derived from serial FEV₁ measurements over 24 h was 0.32 L after 26 weeks of treatment when compared to placebo. The effect was significantly greater for indacaterol/glycopyrronium (Ultibro Breezhaler), when compared to indacaterol, glycopyrronium or tiotropium alone (difference 0.11 L, for each comparison), (serial spirometry subset).
There was no evidence for tachyphylaxis to the effect of indacaterol/glycopyrronium (Ultibro Breezhaler) over time when compared to placebo or its monotherapy components.
Secondary pharmacodynamic effects: The systemic side effects of inhaled beta₂-adrenergic agonists and inhaled muscarinic receptor antagonists are the result of activation of systemic beta₂-adrenergic receptors and blockade of muscarinic receptors after systemic absorption of the drugs. The side effect profile of indacaterol/glycopyrronium (Ultibro Breezhaler) was explored in healthy subjects) and in COPD patients.
Effects on heart rate: Heart rate effects in healthy volunteers were investigated after a single dose of indacaterol/glycopyrronium (Ultibro Breezhaler) 440/200 microgram administered in four dose steps separated by one hour and compared to the effects of placebo, 600 microgram indacaterol, 200 microgram glycopyrronium and 200 microgram salmeterol.
The largest time matched heart rate increase compared to placebo was +5.69 bpm, the largest decrease was -2.51 bpm. Overall the effect on heart rate over time did not show a consistent PD-effect.
Whilst there were no significant effects when indacaterol/glycopyrronium (Ultibro Breezhaler) was compared with indacaterol and glycopyrronium alone, heart rate seemed to be slightly higher (the largest difference being around 11 bpm) after inhalation of 200 microgram salmeterol.
Heart rate in COPD patients at supratherapeutic dose levels was investigated in indacaterol/glycopyrronium (Ultibro Breezhaler) up to doses of 150/100, 300/100 and 600/100 microgram. There were no relevant effects of indacaterol/glycopyrronium (Ultibro Breezhaler) on mean heart rate over 24 h and heart rate assessed after 30 min, 4 h and 24 h.
QT-interval: A thorough QT (TQT) -study in healthy volunteers with doses of inhaled indacaterol up to 600 micrograms did not demonstrate a clinically relevant effect on the QT-interval. Also for glycopyrronium, no QT-prolongation has been observed in a TQT study after an inhaled dose of 400 microgram.
The effects on QTc-interval were investigated in healthy volunteers after inhalation of indacaterol/glycopyrronium (Ultibro Breezhaler) 440/200 microgram in four dose steps separated by one hour. The largest time matched difference versus placebo was 4.62 ms (90% CI 0.40, 8.85 ms), the largest time matched decrease was -2.71 ms (90% CI -6.97, 1.54 ms), indicating that it had no relevant impact on the QT-interval as was expected by the properties of its components.
In COPD patients, doses up to 600/100 microgram of indacaterol/glycopyrronium (Ultibro Breezhaler) also had no apparent influence on the QTc-interval in repeated ECG assessments executed between 15 min and 24 h after dosing. A slightly higher proportion of patients had QTc-prolongations above 450 ms at the indacaterol/glycopyrronium (Ultibro Breezhaler) 600/100 microgram group. The number of notable QTcF changes versus baseline (>30 ms) was similar across all active treatment groups (600/100 microgram, 300/100 microgram, 150/100 microgram and indacaterol 300 microgram), but was lower with placebo.
Serum potassium and blood glucose: In healthy volunteers, after administration of indacaterol/glycopyrronium (Ultibro Breezhaler) 440/200 microgram, the effect on serum potassium was very small (maximal difference -0.14 mmol/L when compared to placebo). The maximal effect on blood glucose was 0.67 mmol/L. When indacaterol/glycopyrronium (Ultibro Breezhaler) 440/200 microgram was compared with 200 microgram salmeterol, the effect on serum potassium (maximum difference 0.21 mmol/L) and blood glucose was smaller (maximum difference 0.21 and 1.19 mmol/L, respectively).
Pharmacokinetics: Absorption: Following inhalation, the median time to reach peak plasma concentrations of indacaterol and glycopyrronium was approximately 15 minutes and 5 minutes, respectively.
Based on the in vitro performance data, the dose of indacaterol delivered to the lung is expected to be similar for indacaterol/glycopyrronium (Ultibro Breezhaler) 110/50 microgram and indacaterol 150 microgram monotherapy product. The steady-state exposure to indacaterol after indacaterol/glycopyrronium (Ultibro Breezhaler) 110/50 microgram inhalation was either similar or slightly lower than systemic exposure after indacaterol 150 microgram monotherapy product inhalation.
Absolute bioavailability of indacaterol after indacaterol/glycopyrronium (Ultibro Breezhaler) 110/50 microgram inhalation ranged from 47% to 66% whereas that of glycopyrronium was about 40%.
The steady-state exposure to glycopyrronium after indacaterol/glycopyrronium (Ultibro Breezhaler) 110/50 microgram inhalation was similar to systemic exposure after glycopyrronium 50 microgram monotherapy product inhalation.
Indacaterol: The median time to reach peak serum concentrations of indacaterol was approximately 15 min after single or repeated inhaled doses.
Indacaterol serum concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, i.e., AUC over the 24-h dosing interval on Day 14 or Day 15 compared to Day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 microgram and 600 microgram.
Glycopyrronium: Following oral inhalation using the glycopyrronium inhaler, glycopyrronium was rapidly absorbed and reached peak plasma levels at 5 minutes post dose.
About 90% of systemic exposure following inhalation is due to lung absorption and 10% is due to gastrointestinal absorption. The absolute bioavailability of orally administered glycopyrronium was estimated to be about 5%.
Following repeated once-daily inhalation in patients with COPD, PK steady-state of glycopyrronium was reached within one week of treatment. The steady-state mean peak and trough plasma concentrations of glycopyrronium for a 50 microgram once-daily dosing regimen were 166 pg/mL and 8 pg/mL, respectively. With once-daily doses of 100 and 200 microgram, steady-state exposure to glycopyrronium (AUC over the dosing interval) was about 1.4-to 1.7-fold higher than after the first dose. Urinary excretion data at steady-state compared to the first dose suggest that systemic accumulation is independent of dose in the dose range of 25 to 200 microgram.
Distribution: Indacaterol: After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 to 2,557 L indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1 to 95.3% and 95.1 to 96.2%, respectively.
Glycopyrronium: After i.v. dosing, the steady-state volume of distribution (Vss) of glycopyrronium was 83 L and the volume of distribution in the terminal phase (Vz) was 376 L. The apparent volume of distribution in the terminal phase following inhalation (Vz/F) was 7310 L, which reflects the much slower elimination after inhalation. The in vitro human plasma protein binding of glycopyrronium was 38% to 41% at concentrations of 1 to 10 ng/mL. These concentrations were at least 6-fold higher than the steady state mean peaks levels achieved in plasma for a 50 micrograms once-daily dosing regimen.
Biotransformation/metabolism: Indacaterol: After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 h. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.
In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.
Glycopyrronium: In vitro metabolism studies showed consistent metabolic pathways for glycopyrronium bromide between animals and humans. No human specific metabolites were found. Hydroxylation resulting in a variety of mono-and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9) were seen.
In vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. The hydrolysis to M9 is likely to be catalyzed by members from the cholinesterase family.
After inhalation, systemic exposure to M9 was on average in the same order of magnitude as the exposure to the parent drug. Since in vitro studies did not show lung metabolism and M9 was of minor importance in the circulation (about 4% of parent drug C_max and AUC) after i.v. administration, it is assumed that M9 is formed from the swallowed dose fraction of orally inhaled glycopyrronium bromide by pre-systemic hydrolysis and/or via first pass metabolism. After inhalation as well as i.v. administration, only minimal amounts of M9 were found in the urine (i.e. ≤ 0.5% of dose). Glucuronide and/or sulfate conjugates of glycopyrronium were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.
In vitro inhibition studies demonstrated that glycopyrronium bromide has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrronium bromide for any of the cytochrome P450 isoenzymes tested as well as for UGT1A1 and the transporters MDR1 and MRP2.
Elimination: Indacaterol: In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 L/h. When compared with the serum clearance of indacaterol of 18.8 to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing ranged from 40 to 56 hours which is consistent with the observed time to steady state of approximately 12 to 15 days.
Glycopyrronium: After i.v. administration of [³H]-labelled glycopyrronium bromide to humans, the mean urinary excretion of radioactivity in 48 h amounted to 85% of the dose. A further 5% of the dose was found in the bile. Thus, mass balance was almost complete.
Renal elimination of parent drug accounts for about 60 to 70% of total clearance of systemically available glycopyrronium whereas non-renal clearance processes account for about 30 to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.
Following inhalation of single and repeated once-daily doses between 50 and 200 microgram glycopyrronium by healthy volunteers and patients with COPD mean renal clearance of glycopyrronium was in the range of 17.4 and 24.4 L/h. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to 20% of the dose was found in urine as parent drug.
Glycopyrronium plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life was much longer after inhalation (33 to 57 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration. The elimination pattern suggests a sustained lung absorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 h after inhalation.
Linearity/non-linearity: Indacaterol: Systemic exposure to indacaterol increased with increasing dose (150 microgram to 600 microgram) in a dose proportional manner. Systemic exposure results from a composite of pulmonary and intestinal absorption.
Glycopyrronium: In COPD patients' systemic exposure as well as total urinary excretion of glycopyrronium at pharmacokinetic steady state increased about dose-proportionally over the dose range of 50 microgram to 200 microgram.
Special populations: Indacaterol/glycopyrronium (Ultibro Breezhaler): A population PK analysis in COPD patients after inhalation of indacaterol/glycopyrronium (Ultibro Breezhaler) indicated no significant effect of age, gender and (lean body) weight on the systemic exposure to indacaterol and glycopyrronium. Lean body weight (which is a function of weight and height) was identified as a covariate. A negative correlation between systemic exposure and lean body-weight (or body weight) was observed; however, no dose adjustment is recommended due to the magnitude of the change or the predictive precision of lean body weight.
Smoking status and baseline FEV₁ had no apparent effect on systemic exposure to indacaterol and glycopyrronium after inhalation of indacaterol/glycopyrronium (Ultibro Breezhaler).
Indacaterol: A population analysis of the effect of age, gender and weight on systemic exposure in COPD patients after inhalation indicated that indacaterol can be used at the recommended dose in all age and weight groups and regardless of gender.
The pharmacokinetics of indacaterol was investigated in two different UGT1A1 genotypes - the fully functional [(TA)₆, (TA)₆] genotype and the low activity [(TA)₇, (TA)₇] genotype (Gilbert's syndrome genotype). The study demonstrated that steady-state AUC and C_max of indacaterol were 1.2-fold higher in the [(TA)₇, (TA)₇] genotype, indicating that systemic exposure to indacaterol is only insignificantly affected by this UGT1A1 genotypic variation.
Glycopyrronium: A population PK analysis of data in COPD patients identified body weight and age as factors contributing to inter-patient variability in systemic exposure. Glycopyrronium 50 microgram once-daily can be used at the recommended dose in all age and body weight groups.
Gender, smoking status and baseline FEV₁ had no apparent effect on systemic exposure.
Hepatic impairment: Based on the clinical PK characteristics of its monotherapy components, it can be used at the recommended dose in patients with mild and moderate hepatic impairment. No data are available for subjects with severe hepatic impairment.
Patients with mild and moderate hepatic impairment showed no relevant changes in C_max or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.
Clinical studies in patients with hepatic impairment have not been conducted. Glycopyrronium is cleared predominantly from the systemic circulation by renal excretion (see Elimination as previously mentioned). Impairment of the hepatic metabolism of glycopyrronium is not thought to result in a clinically relevant increase of systemic exposure.
Renal impairment: Based on the clinical PK characteristics of its monotherapy components, it can be used at the recommended dose in patients with mild to moderate renal impairment. In patients with severe renal impairment or end-stage renal disease requiring dialysis indacaterol/glycopyrronium (Ultibro Breezhaler) should be used only if the expected benefit outweighs the potential risk.
Indacaterol: Due to the very low contribution of the urinary pathway to total body elimination of indacaterol, a study in renally impaired subjects was not performed.
Glycopyrronium: Renal impairment has an impact on the systemic exposure to glycopyrrontium. A moderate mean increase in total systemic exposure (AUC last) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment and up to 2.2-fold in subjects with severe renal impairment and end stage renal disease. Using a population PK analysis, it was concluded that in COPD patients with mild and moderate renal impairment (estimated glomerular filtration rate eGFR ≥30 mL/min/1.73 m²) glycopyrronium can be used at the recommended dose.
Race/Ethnicity: Indacaterol/glycopyrronium (Ultibro Breezhaler): When corrected by lean body weight, no statistically significant effect of ethnicity (Japanese versus non-Japanese) on exposure for both compounds was found.
Indacaterol: No difference between ethnic subgroups was identified. Limited treatment experience is available for the black population.
Glycopyrronium: There were no major differences in total systemic exposure (AUC) between Japanese and Caucasian subjects. Insufficient PK data is available for other ethnicities or races.
Clinical Studies: The Phase III clinical development program [IGNITE] included six studies in which over 8,000 patients were enrolled: one 26-week placebo- and active-controlled (indacaterol 150 microgram once daily, glycopyrronium 50 microgram once daily, open-label tiotropium 18 microgram once daily) study [SHINE]; one 26-week active-controlled (fluticasone/salmeterol 500/50 microgram twice daily) study [ILLUMINATE]; a 64-week active-controlled (glycopyrronium 50 microgram once daily, open-label tiotropium 18 microgram once daily) study [SPARK]; a 52-week placebo-controlled study [ENLIGHTEN]; a 3-week placebo- and active-controlled (tiotropium once daily) exercise tolerance study [BRIGHT]; and a 52-week active-controlled (fluticasone/salmeterol 500/50 microgram twice daily) study [FLAME].
These studies enrolled patients with a clinical diagnosis of moderate to very severe COPD, who were 40 years old or older, and had a smoking history of at least 10 pack years. Of these 5 studies, the [SHINE] and [ENLIGHTEN] studies had a post-bronchodilator FEV₁ <80% and ≥30% of the predicted normal value and a post-bronchodilator FEV₁/FVC ratio of less than 70%. The 26-week active-controlled study, [ILLUMINATE], enrolled patients with a post-bronchodilator FEV₁ of <80% and ≥40% of the predicted normal value. In comparison, the 64-week [SPARK] study enrolled patients with severe to very severe COPD, with a history of ≥1 moderate or severe COPD exacerbation in the previous year, and a post-bronchodilator FEV₁ <50% of the predicted normal value. The 52-week active-controlled study, [FLAME], enrolled moderate to very severe COPD patients with a history of ≥1 moderate or severe COPD exacerbation in the previous year, and a post-bronchodilator FEV₁ of ≥25 and < 60% of the predicted normal value.
Effects on lung function: Indacaterol/glycopyrronium (Ultibro Breezhaler) administered at 110/50 microgram once daily showed clinically meaningful improvements in lung function (as measured by the forced expiratory volume in one second, FEV₁), in a number of clinical studies. In Phase III studies, bronchodilator effects were seen within 5 minutes after the first dose and were maintained over the 24-hour dosing interval from the first dose. Within the 26-week [SHINE] and 52-week [ENLIGHTEN] studies, there was no attenuation of the bronchodilator effect over time.
Trough FEV₁: In the [SHINE] study, it increased post-dose trough FEV₁ by 200 mL compared to placebo at the 26-week primary endpoint (p<0.001) and showed significant increases compared to each monotherapy component treatment arm (indacaterol and glycopyrronium) as well as the tiotropium treatment arm (see Table 1).

The mean pre-dose FEV₁ (average of the values taken at -45 and -15 min prior to the morning dose of study drug) was clinically meaningful and statistically significant in favor of indacaterol/glycopyrronium (Ultibro Breezhaler) at Week 26 compared to fluticasone/salmeterol (100 mL, p<0.001) [ILLUMINATE], at Week 52 compared to placebo (189 mL, p<0.001) [ENLIGHTEN] and at all visits up to Week 64 compared to glycopyrronium (70-80 mL, p-value <0.001) and tiotropium (60-80 mL, p-value <0.001) [SPARK]. In the [FLAME] study, the mean pre-dose FEV₁ was clinically meaningful and statistically significant in favor of indacaterol/glycopyrronium (Ultibro Breezhaler) at all visits up to Week 52 compared to fluticasone/salmeterol (62 86 ml, p<0.001).
Peak FEV₁: Indacaterol/glycopyrronium (Ultibro Breezhaler) produced statistically significant improvement in peak FEV₁ compared to placebo in the first 4 hours post-dose on Day 1 (210 mL, p<0.001), at Week 26 (330 mL, p<0.001), and compared to indacaterol (120 mL), glycopyrronium (130 mL), tiotropium (130 mL) at Week 26 (p<0.001 for all comparisons) [SHINE], and compared to fluticasone/salmeterol on Day 1 (70 mL, p<0.001) and Week 26 (150 mL, p<0.001) [ILLUMINATE].
FEV₁ AUC: Indacaterol/glycopyrronium (Ultibro Breezhaler) increased post-dose FEV₁ AUC_0-12 (primary endpoint) by 140 mL at 26 weeks (p<0.001) in the active-controlled [ILLUMINATE] study compared to fluticasone/salmeterol.
Onset of action: In the [SHINE and ILLUMINATE] studies, indacaterol/glycopyrronium (Ultibro Breezhaler) demonstrated a statistically significant rapid onset of bronchodilator effect on Day 1 and at Week 26. (See Table 2.)

Serial spirometry subset: In the 26-week, placebo-controlled [SHINE] study, 12-hour serial spirometry was performed on Day 1 (Figure 1) and 24-hour serial spirometry at Week 26 (Figure 2) in a subset of 294 patients. Serial FEV₁ values over 12 hours at Day 1 and trough FEV₁ values at Day 2 are shown in Figure 1, and at Week 26 in Figure 2. Improvement of lung function was maintained for 24 hours after the first dose and consistently maintained over the 26-week treatment period with no evidence of tolerance. (See Figures 1 and 2.)

In the [SHINE] serial spirometry subset, indacaterol/glycopyrronium (Ultibro Breezhaler) demonstrated a statistically significant improvement in FEV₁ compared to placebo (400 mL, p<0.001) and tiotropium (160 mL, p<0.001) at 2 hours post-dose at Week 26.
Indacaterol/glycopyrronium (Ultibro Breezhaler) also had clinically meaningful and statistically significant improvements in FEV₁ compared to fluticasone/salmeterol across all time points from 5 minutes post-dose up to 12 hours post-dose at both Week 12 (p<0.001) and Week 26 (p<0.001) [ILLUMINATE] (see Figure 3).

In the [ILLUMINATE] study, indacaterol/glycopyrronium (Ultibro Breezhaler) demonstrated significant overall improvements in lung function compared with fluticasone/salmeterol, across all key subgroups, including age, gender, smoking history, disease severity, and reversibility.
In the [FLAME] serial spirometry subset, indacaterol/glycopyrronium (Ultibro Breezhaler) demonstrated clinically meaningful and statistically significant improvements in FEV₁ AUC_0-12h at 52 weeks of treatment. The Indacaterol/glycopyrronium (Ultibro Breezhaler) group was statistically superior to the fluticasone/salmeterol group from Day 1 onwards (all p<0.05). (See Figure 4.)

Symptomatic outcomes: Breathlessness: Indacaterol/glycopyrronium (Ultibro Breezhaler) significantly reduced breathlessness as evaluated by the Transitional Dyspnoea Index (TDI). Indacaterol/glycopyrronium (Ultibro Breezhaler) demonstrated a clinically meaningful and statistically significant improvement in the TDI focal score at Week 26 as compared to placebo (1.09, p<0.001), tiotropium (0.51, p=0.007) [SHINE], and fluticasone/salmeterol (0.76, p=0.003) [ILLUMINATE].
A significantly higher percentage of patients receiving indacaterol/glycopyrronium (Ultibro Breezhaler) responded with a 1 point or greater improvement in the TDI focal score at Week 26 compared to placebo (68.1% and 57.5% respectively, p=0.004). A higher proportion of patients demonstrated clinically meaningful response at Week 26 on indacaterol/glycopyrronium (Ultibro Breezhaler) as compared to tiotropium (68.1% indacaterol/glycopyrronium vs. 59.2% tiotropium, p=0.016) [SHINE] and fluticasone/salmeterol (65.1% indacaterol/glycopyrronium vs. 55.5% fluticasone/salmeterol, p=0.088) [ILLUMINATE].
Health related quality of life: Indacaterol/glycopyrronium (Ultibro Breezhaler) once daily has also shown a statistically significant effect on health related quality of life measured using the St. George's Respiratory Questionnaire (SGRQ) at 26 weeks as indicated by a reduction in SGRQ total score compared to placebo (-3.01, p=0.002) and tiotropium (-2.13, p=0.009) [SHINE], at 64 weeks compared to tiotropium (-2.69, p<0.001) [SPARK], and at 52 weeks compared to fluticasone/salmeterol (-1.3, p=0.003) [FLAME]. In addition, improvements of the domains of the SGRQ score "symptoms", "activity" and "impact of daily life" were all statistically significant versus tiotropium at Week 64 ("symptoms": -3.06, p=0.003, "activity": -3.14, p < 0.001, "impact of daily life": -2.24, p=0.008) [SPARK].
A higher percentage of patients receiving indacaterol/glycopyrronium (Ultibro Breezhaler) responded with a clinically meaningful improvement in SGRQ score (defined as a decrease of at least 4 units from baseline) at Week 26 compared to placebo (63.7% and 56.6% respectively, p=0.088) and tiotropium (63.7% indacaterol/glycopyrronium vs. 56.4% tiotropium, p=0.047) [SHINE], at Week 64 compared to glycopyrronium and tiotropium (57.3% indacaterol/glycopyrronium vs. 51.8% glycopyrronium, p=0.055; vs. 50.8% tiotropium, p=0.051, respectively) [SPARK], and at Week 52 compared to fluticasone/salmeterol (49.2% indacaterol/glycopyrronium (Ultibro Breezhaler) vs. 43.7% fluticasone/salmeterol, OR: 1.30, p<0.001) [FLAME].
Daily activities: Indacaterol/glycopyrronium (Ultibro Breezhaler) demonstrated a statistically superior improvement versus tiotropium in the percentage of 'days able to perform usual daily activities' over 26 weeks (8.45%, p<0.001) [SHINE] and showed numerical improvement over glycopyrronium (1.87; p=0.195) and statistical improvement over tiotropium (4.95; p=0.001) [SPARK].
COPD exacerbations: At 64 weeks in the [SPARK] study, indacaterol/glycopyrronium (Ultibro Breezhaler) once daily reduced the rate of moderate or severe COPD exacerbations by 12% compared to glycopyrronium (p=0.038) and by 10% compared to tiotropium (p=0.096).
In addition, it was shown to be clinically and statistically superior to glycopyrronium and tiotropium in reducing the rate of all COPD exacerbations (mild, moderate, and severe), with a rate reduction of 15% for indacaterol/glycopyrronium (Ultibro Breezhaler) as compared to glycopyrronium (p=0.001) and 14% as compared to tiotropium (p=0.002).
For time to first moderate or severe COPD exacerbation, indacaterol/glycopyrronium (Ultibro Breezhaler) demonstrated a 7% risk reduction compared to glycopyrronium (p=0.319).
Glycopyrronium and tiotropium showed no difference in risk reduction.
In the 52-week active-controlled [FLAME] study, indacaterol/glycopyrronium (Ultibro Breezhaler) once daily met the primary study objective of non-inferiority in rate of all COPD exacerbations (mild, moderate, or severe) compared to fluticasone/salmeterol. Indacaterol/glycopyrronium (Ultibro Breezhaler) further showed superiority in reducing the annualized rate of all exacerbations by 11% versus fluticasone/salmeterol (3.59 vs. 4.03, p=0.003) and prolonged time-to-first exacerbation with a 16% reduction in risk of an exacerbation (median time: 71 days for indacaterol/glycopyrronium (Ultibro Breezhaler) vs. 51 days for fluticasone/salmeterol, p<0.001).
Indacaterol/glycopyrronium (Ultibro Breezhaler) reduced the annualized rate of moderate or severe exacerbations by 17% versus fluticasone/salmeterol (0.98 vs. 1.19, p<0.001) and prolonged time-to-first moderate or severe exacerbation with a 22% reduction in risk of an exacerbation (25th percentile: 127 days for indacaterol/glycopyrronium (Ultibro Breezhaler) vs. 87 days for fluticasone/salmeterol, p<0.001). Less than 50% of patients in the indacaterol/glycopyrronium (Ultibro Breezhaler) group had an exacerbation, therefore the time to the first moderate or severe exacerbation in the first quartile of patients was calculated instead.
Indacaterol/glycopyrronium (Ultibro Breezhaler) numerically reduced the annualized rate of severe exacerbations by 13% versus fluticasone/salmeterol (0.15 vs. 0.17, p=0.231). Indacaterol/glycopyrronium (Ultibro Breezhaler) prolonged time-to-first severe exacerbation with a 19% reduction in risk of an exacerbation (p=0.046).
The incidence of pneumonia (as confirmed by radiographic imaging i.e. chest x-ray or CT scan) was 3.2% in the indacaterol/glycopyrronium (Ultibro Breezhaler) arm compared to 4.8% in the fluticasone/salmeterol arm (p=0.017). Time to first pneumonia was prolonged with indacaterol/glycopyrronium (Ultibro Breezhaler) compared to fluticasone/salmeterol (p=0.013).
Use of rescue medication: Over 26 weeks, indacaterol/glycopyrronium (Ultibro Breezhaler) once daily significantly reduced the use of rescue medication (salbutamol) by 0.96 puffs per day (p<0.001) compared to placebo and 0.54 puffs/day (p <0.001) compared to tiotropium in the [SHINE] study, as well as 0.39 puffs per day (p=0.019) compared to fluticasone/salmeterol in the [ILLUMINATE] study.
Over 64 weeks, indacaterol/glycopyrronium (Ultibro Breezhaler) reduced the use of rescue medication (salbutamol) by 0.76 puffs per day (p<0.001) compared to tiotropium in the [SPARK] study.
Over 52 weeks, indacaterol/glycopyrronium (Ultibro Breezhaler) once daily reduced the use of rescue medication by 1.01 puffs per day from baseline and fluticasone/salmeterol had a reduction of 0.76 puffs per day from baseline. The difference of 0.25 puffs per day was statistically significant (p<0.001).
Exercise tolerance: In a 3-week study [BRIGHT] where exercise tolerance was tested via cycle ergometry at submaximal (75%) workload (submaximal exercise tolerance test), indacaterol/glycopyrronium (Ultibro Breezhaler), dosed in the morning, reduced dynamic hyperinflation and improved the length of time exercise could be maintained from the first dose onwards. On the first day of treatment, inspiratory capacity under exercise was significant improved (250 mL, p<0.001) compared to placebo. After three weeks of treatment, the improvement in inspiratory capacity with indacaterol/glycopyrronium (Ultibro Breezhaler) was greater (320 mL, p<0.001) and exercise endurance time increased (59.5 seconds, p=0.006) compared to placebo. Similar findings were seen with tiotropium.
Whole-Body Plethysmography measurements of Residual volume (RV) and Functional Residual Capacity (FRC) give insights on airway closure and reflects the presence of gas trapping, considered a hallmark of COPD. On the first day of treatment, 60 min post-dose, indacaterol/glycopyrronium (Ultibro Breezhaler) reduced RV by 380 mL (p<0.001) compared to placebo and FRC by 350 mL p< 0.001) compared to placebo. On day 21, 60 min post-dose, further reductions were seen with RV by 520 mL (p< 0.001) and FRC by 520 mL (p< 0.001).
Toxicology: Non-Clinical Safety Data: Information related to indacaterol/glycopyrronium (Ultibro Breezhaler): A bridging toxicology program was performed for indacaterol/glycopyrronium (Ultibro Breezhaler) that included in vitro and in vivo safety pharmacology assessments, 2-week inhalation toxicity studies in rats and dogs, a 13-week inhalation toxicity study in dogs and an inhalation embryo-fetal development study in rats. Increased heart rates were apparent after the administration of each individual monotherapy and indacaterol/glycopyrronium (Ultibro Breezhaler) during cardiovascular safety pharmacology or repeated-dose toxicity studies in dogs. The effects on heart rate increased in magnitude and duration when compared with the changes observed for each component alone consistent with an additive response. The highest doses of indacaterol administered alone or in combination were associated with a similar incidence and severity of papillary muscle lesions in the heart of a few individuals during the 2-week toxicity study in dogs. Shortening of PR, P width, QT that reflected increased heart rate and decreased systolic and diastolic blood pressure were also apparent following treatment with indacaterol/glycopyrronium (Ultibro Breezhaler) during the cardiovascular safety pharmacology study in dogs. An estimation of the safety margin is based on papillary muscle lesions in the heart of dogs as the most sensitive species. The NOAEL of 0.386/0.125 mg/kg/day (indacaterol/glycopyrronium) in the 13-week toxicity study was devoid of heart lesions and corresponds with systemic exposures based on mean AUC0-24h values of approximately 64 and 59-fold higher than seen in humans at a dose of 110/50 micrograms (indacaterol/glycopyrronium), for each component respectively.
Information related to indacaterol: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. The effects of indacaterol seen in toxicity studies in dogs were mainly on the cardiovascular system and consisted of tachycardia, arrhythmias and myocardial lesions. These effects are known pharmacological effects and could be explained by the beta₂-agonistic properties of indacaterol. Other relevant effects noted in repeated-dose toxicity studies were mild irritancy of the upper respiratory tract in rats consisting of rhinitis and epithelial changes of the nasal cavity and larynx. All these findings were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Studies on genotoxicity did not reveal any mutagenic or clastogenic potential. The carcinogenic potential of indacaterol has been evaluated in a 2-year inhalation study in rats and a 26-week oral transgenic mouse study. Lifetime treatment of rats resulted in increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle at doses approximately 30-times the dose of 150 microgram once-daily for humans (based on AUC0-24h). Increases in leiomyomas of the rat female genital tract have been similarly demonstrated with other beta₂-adrenergic agonist drugs. A 26-week oral study in CB6F1/TgrasH2 hemizygous mice with indacaterol did not show any evidence of tumorigenicity at doses of at least 103-times the dose of 150 microgram once-daily for humans (based on AUC0-24h).
Information related to glycopyrronium: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.
The effects seen during repeated-dose inhalation toxicity studies were attributable to exacerbations of the expected pharmacological action of glycopyrronium or mild local irritation. These included mild to moderate increases in heart rate in dogs and a number of reversible changes in rat and dogs associated with reduced secretions from the salivary, lacrimal and Harderian glands and pharynx. Lens opacities observed during chronic studies in rats have been described for other muscarinic antagonists and are considered to be species-specific changes with limited relevance for therapeutic use in patients. Findings in the respiratory tract of rats included degenerative/regenerative changes and inflammation in the nasal cavity and larynx that are consistent with mild local irritation. Minimal epithelial changes in the lung at the bronchioloalveolar junction were also observed in rats and are regarded as a mild adaptive response. All these findings were observed at exposures considered to be sufficiently in excess of the maximum human exposure and therefore indicate limited relevance during clinical use.
Genotoxicity studies did not reveal any mutagenic or clastogenic potential for glycopyrronium. Carcinogenicity studies in transgenic mice using oral administration and in rats using inhalation administration revealed no evidence of carcinogenicity at systemic exposures (AUC0-24h) of approximately 53-fold higher in mice and 75-fold higher in rats than the dose of 50 microgram once-daily for humans.