Ultibro Breezhaler Special Precautions

Ultibro Breezhaler should not be administered concomitantly with products containing other long-acting beta-adrenergic agonists or long-acting muscarinic antagonists, drug classes to which the components of Ultibro Breezhaler belong (see Interactions).
Asthma and mixed airways disease: Ultibro Breezhaler should not be used for the treatment of asthma due to the absence of data in this indication.
Indacaterol, one of the active ingredients of Ultibro Breezhaler, belongs to the class of long-acting beta₂-agonists. Long-acting beta₂-adrenergic agonists may increase the risk of asthma-related serious adverse events, including asthma-related deaths, when used for the treatment of asthma.
A differential diagnosis should be made to exclude asthma or mixed airways disease before initiating Ultibro Breezhaler. See Pharmacology: Pharmacodynamics under Actions for clinical experience to date.
Not for acute use: Ultibro Breezhaler is not indicated for the treatment of acute episodes of bronchospasm.
Hypersensitivity: Immediate hypersensitivity reactions have been reported after administration of indacaterol or glycopyrronium, which are components of Ultibro Breezhaler. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of tongue, lips and face), urticaria, or skin rash, Ultibro Breezhaler should be discontinued immediately and alternative therapy instituted.
Paradoxical bronchospasm: As with other inhalation therapy, 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 effect to glycopyrronium: Like other anticholinergic containing drugs, Ultibro Breezhaler should be used with caution in patients with narrow-angle glaucoma or urinary retention.
Patients should be advised about signs and symptoms of acute narrow-angle glaucoma and should be informed to stop using Ultibro Breezhaler and to contact their doctor immediately should any of these signs or symptoms develop.
Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a doctor immediately should any of these signs or symptoms develop.
Systemic effects of beta-agonists: Although no clinically relevant effect on the cardiovascular system is usually seen after the administration of Ultibro Breezhaler at the recommended dose, as with other compounds containing a beta₂-adrenergic agonist, Ultibro Breezhaler should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta₂-adrenergic agonists.
As with other drugs containing an inhaled beta₂-adrenergic agonist, Ultibro Breezhaler should not be used more often or at higher doses than recommended.
Cardiovascular effects: Ultibro Breezhaler should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension).
Beta₂-adrenergic agonists may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occur with this medicinal product, treatment may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce electrocardiographic (ECG) changes, such as flattening of the T wave, prolongation of QT interval and ST segment depression, although the clinical significance of these observations 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.
Patients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc (Fridericia method) was prolonged (>450 ms) were excluded from the clinical trials, and therefore there is no experience in these patient groups. Ultibro Breezhaler should be used with caution in these patient groups.
Hypokalaemia with beta-agonists: Beta₂-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment (see Interactions) which may increase the susceptibility to cardiac arrhythmias.
Clinically relevant effects of hypokalemia have not been observed in clinical studies of Ultibro Breezhaler at the recommended therapeutic dose (see Pharmacology: Pharmacodynamics under Actions).
Hyperglycaemia with beta-agonists: Inhalation of high doses of beta₂-adrenergic agonists may produce increases in plasma glucose. Upon initiation of treatment with Ultibro Breezhaler plasma glucose should be monitored more closely in diabetic patients. During long-term clinical studies ([ENLIGHTEN] and [RADIATE]), more patients on Ultibro Breezhaler experienced clinically notable changes in blood glucose (4.9%) than on placebo (2.7%). Ultibro Breezhaler has not been investigated in patients for whom diabetes mellitus is not well controlled.
Use in the renal impairment: For 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, Ultibro Breezhaler should be used only if the expected benefit outweighs the potential risk (see Pharmacology: Pharmacokinetics under Actions). These patients should be monitored closely for potential adverse drug reactions.
Use in 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, therefore caution should be observed in these patients (see Pharmacology: Pharmacokinetics under Actions).
Effects on laboratory tests: No data available.
Genotoxicity: Information related to indacaterol: Indacaterol was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including bacterial reverse mutation, chromosomal aberrations in Chinese hamster V79 cells and the rat bone marrow micronucleus test.
Information related to glycopyrronium: Glycopyrronium bromide was not genotoxic in assays for bacterial mutagenicity, chromosomal aberrations in vitro (human lymphocytes) or in vivo clastogenicity (rat bone marrow micronucleus test).
Carcinogenicity: No carcinogenicity studies have been conducted with indacaterol and glycopyrronium in combination.
Information related to indacaterol: The carcinogenic potential of indacaterol has been evaluated in a 26-week oral gavage study in transgenic mice (CB6F1/TgrasH2) and a 2-year inhalation study in rats. No carcinogenicity was observed in mice at doses up to 600 mg/kg/day (approximately 200 times in males and 425-times in females the AUC in humans at the maximum recommended clinical dose of 110 µg/day with use of Ultibro Breezhaler). Lifetime treatment of rats at 2.1 mg/kg/day (relative exposure, 57) resulted in increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in females. Increases in leiomyomas of the rat female genital tract have been similarly demonstrated with other β₂-adrenergic agonist drugs. Their development is consistent with proliferation in response to prolonged relaxation of the smooth muscle (pharmacologically mediated), and the finding is not considered to indicate a carcinogenic hazard to patients. Squamous metaplasia was observed in the upper respiratory tract tissues of mice, rats and dogs following inhalation administration of indacaterol. This finding is consistent with an adaptive response to irritation and occurred at large multiples of the human dose. It is not considered to indicate a carcinogenic hazard to humans with the therapeutic use of indacaterol. No data are available to determine whether exposure to tobacco smoke enhances the respiratory tract toxicity of indacaterol.
Information related to glycopyrronium: Carcinogenicity studies of six months duration in transgenic mice (rasH2) using oral administration and 2 years duration in rats using inhalation administration revealed no evidence of carcinogenicity with glycopyrronium bromide. The highest dose levels employed (75 and 100 mg/kg/day in male and female mice and 0.45 mg/kg/day in rats) were associated with systemic exposures (AUC) of approximately 53-fold higher in mice and 79-fold higher in rats than in humans at the maximum recommended dose of 50 μg once-daily. The lung deposited dose in rats (per unit alveolar surface area) was up to almost 200-fold higher than the level anticipated in patients.
Effects on Ability to Drive and Use Machines: The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Use in the elderly: Ultibro Breezhaler can be used at the recommended dose in elderly patients 75 years of age and older.
Use in children: Ultibro Breezhaler should not be used in patients under 18 years of age, COPD is an indication of adults only.