ZIMBUS BREEZHALER Inhalation powder (hard capsule) Ref.[50544] Active ingredients: Glycopyrronium Indacaterol Mometasone

Deterioration of disease

This medicinal product should not be used to treat acute asthma symptoms, including acute episodes of bronchospasm, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.

Patients should not stop treatment without physician supervision since symptoms may recur after discontinuation.

It is recommended that treatment with this medicinal product should not be stopped abruptly. If patients find the treatment ineffective, they should continue treatment but must seek medical attention. Increasing use of reliever bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy. Sudden and progressive deterioration in the symptoms of asthma is potentially life-threatening and the patient should undergo urgent medical assessment.

Hypersensitivity

Immediate hypersensitivity reactions have been observed after administration of this medicinal product. If signs suggesting allergic reactions occur, in particular angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips and face), urticaria or skin rash, treatment should be discontinued immediately and alternative therapy instituted.

Paradoxical bronchospasm

As with other inhalation therapy, administration of this medicinal product may result in paradoxical bronchospasm, which can be life-threatening. If this occurs, treatment should be discontinued immediately and alternative therapy instituted.

Cardiovascular effects

Like other medicinal products containing beta₂-adrenergic agonists, this medicinal product may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. If such effects occur, treatment may need to be discontinued.

This medicinal product should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta₂-adrenergic agonists.

Patients with unstable ischaemic heart disease, a history of myocardial infarction in last 12 months, New York Heart Association (NYHA) class III/IV left ventricular failure, arrhythmia, uncontrolled hypertension, cerebrovascular disease, history of long QT syndrome and patients being treated with medicinal products known to prolong QTc were excluded from studies in the indacaterol/glycopyrronium/mometasone furoate clinical development programme. Thus safety outcomes in these populations are considered unknown.

While beta₂-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, the clinical significance of these findings is unknown.

Long-acting beta₂-adrenergic agonists (LABA) or LABA-containing combination products such as Zimbus Breezhaler should therefore be used with caution in patients with known or suspected prolongation of the QT interval or who are being treated with medicinal products affecting the QT interval.

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 asthma, hypokalaemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility to cardiac arrhythmias (see section 4.5).

Clinically relevant hypokalaemia has not been observed in clinical studies of indacaterol/glycopyrronium/mometasone furoate at the recommended therapeutic dose.

Hyperglycaemia

Inhalation of high doses of beta₂-adrenergic agonists and corticosteroids may produce increases in plasma glucose. Upon initiation of treatment, plasma glucose should be monitored more closely in diabetic patients.

This medicinal product has not been investigated in patients with Type I diabetes mellitus or uncontrolled Type II diabetes mellitus.

Anticholinergic effect related to glycopyrronium

Like other anticholinergic medicinal products, this medicinal product 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 instructed to stop treatment and to contact their doctor immediately should any of these signs or symptoms develop.

Patients with severe 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, caution should be observed (see sections 4.2 and 5.2).

Prevention of oropharyngeal infections

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

Systemic effects of corticosteroids

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations.

Possible systemic effects may include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataracts, glaucoma, and, more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is therefore important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Visual disturbance may be reported with systemic and topical (including intranasal, inhaled and intraocular) corticosteroid use. Patients presenting with symptoms such as blurred vision or other visual disturbances should be considered for referral to an ophthalmologist for evaluation of possible causes of visual disturbances, which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

This medicinal product should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections.

Excipients

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

No specific interaction studies were conducted with indacaterol/glycopyrronium/mometasone furoate. Information on the potential for interactions is based on the potential for each of the monotherapy components.

Medicinal products known to prolong the QTc interval

Like other medicinal products containing a beta₂-adrenergic agonist, this medicinal product should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or medicinal products known to prolong the QT interval, as any effect of these on the QT interval may be potentiated. Medicinal products known to prolong the QT interval may increase the risk of ventricular arrhythmia (see sections 4.4 and 5.1).

Hypokalaemic treatment

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta₂-adrenergic agonists (see section 4.4).

Beta-adrenergic blockers

Beta-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists. Therefore, this medicinal product should not be given together with beta-adrenergic blockers unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution.

Interaction with CYP3A4 and P-glycoprotein inhibitors

Inhibition of CYP3A4 and P-glycoprotein (P-gp) has no impact on the safety of therapeutic doses of Zimbus Breezhaler.

Inhibition of the key contributors of indacaterol clearance (CYP3A4 and P-gp) or mometasone furoate clearance (CYP3A4) raises the systemic exposure of indacaterol or mometasone furoate up to two-fold.

Due to the very low plasma concentration achieved after inhaled dosing, clinically significant interactions with mometasone furoate are unlikely. However, there may be a potential for increased systemic exposure to mometasone furoate when strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, nelfinavir, ritonavir, cobicistat) are co-administered.

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%. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.

Other long-acting antimuscarinics and long-acting beta₂-adrenergic agonists

The co-administration of this medicinal product with other medicinal products containing long-acting muscarinic antagonists or long-acting beta₂-adrenergic agonists has not been studied and is not recommended as it may potentiate adverse reactions (see sections 4.8 and 4.9).

Pregnancy

There are insufficient data from the use of Zimbus Breezhaler or its individual components (indacaterol, glycopyrronium and mometasone furoate) in pregnant women to determine whether there is a risk.

Indacaterol and glycopyrronium were not teratogenic in rats and rabbits following subcutaneous or inhalation administration, respectively (see section 5.3). In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoate caused increased foetal malformations and decreased foetal survival and growth.

Like other medicinal products containing beta₂-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle.

This medicinal product should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus.

Breast-feeding

There is no information available on the presence of indacaterol, glycopyrronium or mometasone furoate in human milk, on the effects on a breast-fed infant, or on the effects on milk production. Other inhaled corticosteroids similar to mometasone furoate are transferred into human milk. Indacaterol, glycopyrronium and mometasone furoate have been detected in the milk of lactating rats. Glycopyrronium reached up to 10-fold higher concentrations in the milk of lactating rats than in the blood of the dam after intravenous administration.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Reproduction studies and other data in animals did not indicate a concern regarding fertility in either males or females.

This medicinal product has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions over 52 weeks were asthma (exacerbation) (41.8%), nasopharyngitis (10.9%), upper respiratory tract infection (5.6%) and headache (4.2%).

Tabulated list of adverse reactions

Adverse drug reactions (ADRs) are listed by MedDRA system organ class (Table 1). The frequency of the ADRs is based on the IRIDIUM study. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 1. Adverse reactions:

^* Indicates grouping of preferred terms (PTs):
¹ Oral candidiasis, oropharyngeal candidiasis.
² Asymptomatic bacteriuria, bacteriuria, cystitis, urethritis, urinary tract infection, urinary tract infection viral.
³ Drug eruption, drug hypersensitivity, hypersensitivity, rash, rash pruritic, urticaria.
⁴ Blood glucose increased, hyperglycaemia.
⁵ Headache, tension headache.
⁶ Sinus tachycardia, supraventricular tachycardia, tachycardia.
⁷ Odynophagia, oropharyngeal discomfort, oropharyngeal pain, throat irritation.
⁸ Chronic gastritis, enteritis, gastritis, gastroenteritis, gastrointestinal inflammation.
⁹ Dry mouth, dry throat.
¹⁰ Drug eruption, rash, rash papular, rash pruritic.
¹¹ Eye pruritus, pruritus, pruritus genital.
¹² Back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.