Ultibro Breezhaler 110/ 50 μg Dry powder inhalation capsules

ULTIBRO BREEZHALER is indicated for the treatment of chronic obstructive pulmonary disease (COPD) in patients who are still symptomatic despite treatment with a long acting u03b22 adrenergic agonist (LABA) or a long acting muscarinic antagonist (LAMA).

General target population
The recommended dosage of ULTIBRO BREEZHALER is the once-daily inhalation of the content of one 110/50 microgram capsule using the ULTIBRO BREEZHALER inhaler.

Dosing in special populations
Renal impairment
ULTIBRO BREEZHALER can be used at the recommended dose in patients with mild to moderate renal impairment. ULTIBRO BREEZHALER has not been studied in patients with severe renal impairment or end-stage renal disease requiring dialysis and no dosage recommendations can be made.
Hepatic impairment
ULTIBRO BREEZHALER 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 (see Pharmacokinetics, Special Populations u2013 Patients with hepatic impairment).
Paediatrics
ULTIBRO BREEZHALER should not be used in patients under 18 years of age.
Elderly
ULTIBRO BREEZHALER can be used at the recommended dose in elderly patients 75 years of age and older without significant renal impairment.
Method of administration
ULTIBRO BREEZHALER capsules must be administered only by the oral inhalation route and only using the ULTIBRO BREEZHALER inhaler. ULTIBRO BREEZHALER capsules must not be swallowed (see Known Symptoms of Overdosage and Particulars of its Treatment). ULTIBRO BREEZHALER should be administered at the same time of the day each day. If a dose is missed, it should be taken as soon as possible on the same day. Patients should be instructed not to take more than one dose in a day. ULTIBRO BREEZHALER capsules must always be stored in the blister to protect from moisture, and only removed IMMEDIATELY BEFORE USE (see Storage Instructions).

ULTIBRO BREEZHALER is contraindicated in patients with hypersensitivity to indacaterol, glycopyrronium, lactose or to any of the excipients.

ULTIBRO BREEZHALER should not be administered concomitantly with products containing other long-acting beta-adrenergic agonists or long-acting muscarinic antagonists, medicine classes to which the components of ULTIBRO BREEZHALER belong (see Interactions).
Asthma
ULTIBRO BREEZHALER should not be used for the treatment of asthma.
Not for acute use
ULTIBRO BREEZHALER is not indicated for the treatment of acute episodes of bronchospasm.
Hypersensitivity related to indacaterol
Immediate hypersensitivity reactions have been reported after administration of indacaterol, one of the components of ULTIBRO BREEZHALER. If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, ULTIBRO BREEZHALER should be discontinued immediately and alternative therapy instituted.
Paradoxical bronchospasm
Administration of ULTIBRO BREEZHALER may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, ULTIBRO BREEZHALER should be discontinued immediately and alternative therapy instituted.
Anticholinergic effects related to glycopyrronium
ULTIBRO BREEZHALER should be used with caution in patients with narrow-angle glaucoma or urinary outflow tract obstruction e.g. due to benign prostatic hypertrophy as urinary retention may occur. Patients should be advised about signs and symptoms of acute narrow-angle glaucoma and of urinary outflow tract obstruction and should be informed to stop using ULTIBRO BREEZHALER and to contact their doctor immediately should any of these signs or symptoms develop.
Patients with severe renal impairment
Patients with severe renal impairment (estimated glomerular filtration rate below 30 ml/min/1.73 m2) including those with end-stage renal disease requiring dialysis, have not been studied using ULTIBRO BREEZHALER. Hence the use of ULTIBRO BREEZHALER is not recommended for these patients.
Systemic effects of beta-agonists
ULTIBRO BREEZHALER should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac dysrhythmias, hypertension), in patients with convulsive disorders, hyperthyroidism or diabetes mellitus, and in patients who are unusually responsive to beta 2-adrenergic agonists. ULTIBRO BREEZHALER should not be used more often or at higher doses than recommended.
Cardiovascular effects of beta-agonists
ULTIBRO BREEZHALER may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In such cases the medicine may need to be discontinued. In addition, beta-adrenergic agonists, such as indacaterol, have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QT interval and ST segment depression. The clinical significance of these findings is unknown. Therefore, long-acting beta2-adrenergic agonists (LABA) or LABA containing products such as ULTIBRO BREEZHALER should be used with caution in patients with known or suspected prolongation of the QT interval or patients treated with medicinal products affecting the QT interval.
Hypokalaemia with beta-agonists
Beta 2-adrenergic agonists, such as indacaterol may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment (see Interactions) which may increase the susceptibility to cardiac dysrhythmias.
Hyperglycaemia with beta-agonists
Inhalation of high doses of beta 2-adrenergic agonists, such as indacaterol, may produce increases in plasma glucose. Upon initiation of treatment with ULTIBRO BREEZHALER plasma glucose should be monitored more closely in diabetic patients. During clinical studies, more patients on ULTIBRO BREEZHALER experienced clinically notable changes in blood glucose (4.1%) at the recommended dose than on placebo (2.3%). ULTIBRO BREEZHALER has not been investigated in patients for whom diabetes mellitus is not well controlled.
Lactose
ULTIBRO BREEZHALER contains lactose. Patients with the rare hereditary condition of lactose or galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not use ULTIBRO BREEZHALER. ULTIBRO BREEZHALER contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus.

Interactions linked to the ULTIBRO BREEZHALER
Concomitant administration of orally inhaled indacaterol and glycopyrronium under steady-state conditions of both medicines did not affect the pharmacokinetics (PK) of either medicine.
Interactions linked to indacaterol
Anticipated interactions resulting in concomitant use not being recommended
Beta-adrenergic blockers may weaken or antagonise the effect of beta 2-adrenergic agonists, such as indacaterol. Therefore ULTIBRO BREEZHALER should not be given together with beta-adrenergic blockers (including eye drops).
Medicines known to prolong QTc interval
ULTIBRO BREEZHALER should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or medicines known to prolong the QT interval, as any effect of these on the QT interval may be potentiated. Medicines known to prolong the QT-interval may increase the risk of ventricular dysrhythmia (see Warnings and Special Precautions).
Sympathomimetic medicines
Concomitant administration of other sympathomimetic medicines (alone or as part of combination therapy e.g. as in medicines used for colds and flu) may potentiate the undesirable effects of indacaterol (see Warnings and Special Precautions).
Hypokalaemia
Concomitant treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta 2-adrenergic agonists, such as indacaterol (see Warnings and Special Precautions).
Observed interactions to be considered
Data suggest that systemic clearance is influenced by modulation of both P-gp and CYP3A4 activities and that a 2-fold AUC increase reflects the impact of maximal combined inhibition.
Interactions linked to glycopyrronium
Anticipated interactions resulting in concomitant use not being recommended
The co-administration of ULTIBRO BREEZHALER with inhaled anticholinergic-containing medicines has not been studied and is therefore not recommended.
Observed interactions to be considered
Cimetidine or other inhibitors of organic cation transport. In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport which is thought to contribute to the renal excretion of glycopyrronium, increased total exposure (AUC) to glycopyrronium by 22% and decreased renal clearance by 23%.

Safety in pregnancy and lactation has not been demonstrated. Labour and delivery Information related to indacaterol ULTIBRO BREEZHALER may inhibit labour due to a relaxant effect on uterine smooth muscle.

ULTIBRO BREEZHALER may have an influence on the ability of patients to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue, dizziness or vertigo during treatment with ULTIBRO BREEZHALER (see section 4.8).

Summary of the safety profile The safety experience with ULTIBRO BREEZHALER was comprised of exposure of up to 15 months at the recommended therapeutic dose (110/50 u03bcg). The ULTIBRO BREEZHALER Phase III clinical development programme consisted of 6 key studies and enrolled over 6 000 patients with a clinical diagnosis of moderate to very severe COPD. Safety data from 5 of these studies with treatment durations of 12 weeks or longer were pooled from 1 805 patients exposed to ULTIBRO BREEZHALER 110/50 u03bcg once-daily. The frequency category for each adverse medicine reaction is based on the following convention (CIOMS III): very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000, < 1/1 000); very rare (< 1/10 000), including isolated reports. ULTIBRO BREEZHALER showed similar adverse medicine reactions as the individual components. As ULTIBRO BREEZHALER contains indacaterol and glycopyrronium, the type and severity of adverse reactions associated with each of the components may be expected in the combination.
Adverse medicine reactions observed with ULTIBRO BREEZHALER in two placebo-controlled clinical trials Adverse drug reactions Indacaterol/ glycopyrronium 110/50 u03bcg once daily N=1106 Rate (95% CI) Placebo N=748 Rate (95% CI) Frequency category Infections and infestations Upper respiratory tract infection 16.96 (14.53, 19.74) 19.64 (16.67, 23.06) Very common Nasopharyngitis 9.03 (7.26, 11.20) 8.78 (6.77, 11.37) Common Urinary tract infection 2.86 (1.91, 4.29) 1.49 (0.80, 2.75) Common Sinusitis 1.8 (1.11, 2.93) 1.54 (0.82, 2.88) Common Rhinitis 1.86 (1.16, 2.99) 2.98 (1.16, 2.99) Common Immune system disorders Hypersensitivity 2.06 (1.31, 3.21) 1.90 (1.04, 3.47) Common Metabolism and nutrition disorders Hyperglycaemia and diabetes mellitus 1.65 (0.92, 2.95) 2.42 (1.46, 4.00) Common Psychiatric disorders Insomnia 0.81 (0.37, 1.76) 0.98 (0.44, 2.21) Uncommon Nervous system disorders Dizziness 1.74 (1.05, 2.88) 0.95 (0.42, 2.14) Common Headache 3.24 (2.28, 4.60) 2.66 (1.64, 4.29) Common Paraesthesia 0.09 (0.01, 0.64) (0) Rare Eye disorders Glaucoma* 0.19 (0.05, 0.75) (0) Uncommon Cardiac disorders Ischaemic heart disease 0.67 (0.32, 1.41) 0.78 (0.29, 2.12) Uncommon Atrial fibrillation 0.8 (0.33, 1.95) 0.24 (0.03, 1.68) Uncommon Tachycardia 0.39 (0.15, 1.04) 0.7 (0.29, 1.66) Uncommon Palpitations 0.73 (0.34, 1.56) 1.38 (0.68, 2.80) Uncommon Respiratory, thoracic and mediastinal disorders Cough 6.84 (5.38, 8.68) 5.94 (4.30, 8.17) Common Oropharyngeal pain including throat irritation 2.95 (2.05, 4.23) 2.71 (1.70, 4.29) Common Epistaxis 0.28 (0.09, 0.85) 0.24 (0.03, 1.68) Uncommon Paradoxical bronchospasm 0.18 (0.05, 0.73) 0.51 (0.16, 1.64) Uncommon Gastrointestinal disorders Dyspepsia 2.29 (1.49, 3.51) 2.25 (1.32, 3.81) Common Dental caries 1.39 (0.79, 2.44) 0.97 (0.43, 2.19) Common Dry mouth 0.64 (0.31, 1.34) 0.45 (0.14, 1.39) Uncommon Gastroenteritis 0.28 (0.06, 1.18) 0.97 (0.43, 2.18) Uncommon Skin and subcutaneous tissue disorders Pruritus/rash 0.56 (0.25, 1.25) 0.91 (0.37, 2.24) Uncommon Musculoskeletal and connective tissue disorders Musculoskeletal pain 0.92 (0.47, 1.81) 1.3 (0.60, 2.78) Uncommon Muscle spasm 0.85 (0.41, 1.73) 0.44 (0.14, 1.37) Uncommon Pain in extremity 0.74 (0.37, 1.47) 0.14 (0.02, 0.98) Uncommon Myalgia 0.57 (0.25, 1.26) 0.53 (0.17, 1.70) Uncommon Renal and urinary disorders Bladder obstruction and urinary retention 1.03 (0.52, 2.03) (0) Common General disorders and administration site conditions Pyrexia* 1.96 (1.26, 3.05) 1.47 (0.79, 2.72) Common Chest pain 1.85 (1.13, 3.02) 1.5 (0.77, 2.92) Common Peripheral oedema 0.65 (0.28, 1.48) 1.09 (0.51, 2.33) Uncommon Fatigue 0.83 (0.41, 1.68) 0.54 (0.20, 1.43) Uncommon Of the 1106 patients on ULTIBRO BREEZHALER, 946 (86%) were exposed for at least 26 weeks, and 447 (40%) were exposed for at least 52 weeks. Of the 748 patients on placebo, 588 (79%) were exposed for at least 26 weeks, and 339 (45%) were exposed for at least 52 weeks. *adverse drug reaction observed with the combination ULTIBRO BREEZHALER but not with the monotherapy components. Post marketing: Spontaneous reports: The following adverse medicine reactions have been reported with ULTIBRO BREEZHALER in post-marketing experience. Immune system disorders Angioedema Respiratory, thoracic and mediastinal disorders Dysphonia Additional information on individual components Adverse medicine reactions are presented below for each component of ULTIBRO BREEZHALER. Additional adverse reactions previously reported with one of the individual components may occur with ULTIBRO BREEZHALER even if not observed in the pivotal clinical trials. Indacaterol Nasopharyngitis, headache, sinusitis, muscle spasm, rhinorrhea, peripheral oedema, myalgia, ischaemic heart disease, pruritus/rash, diabetes and hyperglycaemia, atrial fibrillation, hypersensitivity, paraesthesia, tachycardia, paradoxical bronchospasm. Glycopyrronium Dry mouth, gastroenteritis, insomnia, pain in extremity, rash, fatigue, asthenia, sinus congestion, rhinitis, hyperglycaemia, hypoesthesia and atrial fibrillation.

Treatment should be supportive and symptomatic.