ONBREZ BREEZHALER Inhalation powder, hard capsule Ref.[7869] Active ingredients: Indacaterol

Asthma

Onbrez Breezhaler is a long-acting beta₂-adrenergic agonist, which is only indicated for COPD and should not be used in asthma due to the absence of long-term outcome data in asthma.

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.

Hypersensitivity

Immediate hypersensitivity reactions have been reported after administration of Onbrez Breezhaler. If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, Onbrez Breezhaler should be discontinued immediately and alternative therapy instituted.

Paradoxical bronchospasm

As with other inhalation therapy, administration of Onbrez Breezhaler may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs Onbrez Breezhaler should be discontinued immediately and alternative therapy substituted.

Deterioration of disease

Onbrez Breezhaler is not indicated for the treatment of acute episodes of bronchospasm, i.e. as rescue therapy. In the event of deterioration of COPD during treatment with Onbrez Breezhaler, a re- evaluation of the patient and of the COPD treatment regimen should be undertaken. An increase in the daily dose of Onbrez Breezhaler beyond the maximum dose of 300 microgram is not appropriate.

Systemic effects

Although no clinically relevant effect on the cardiovascular system is usually seen after the administration of Onbrez Breezhaler at the recommended doses, as with other beta₂-adrenergic agonists, indacaterol 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.

Cardiovascular effects

Like other beta₂-adrenergic agonists, indacaterol 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, treatment may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce electrocardiogram (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 such as Onbrez Breezhaler should be used with caution in patients with known or suspected prolongation of the QT interval or treated with medicinal products affecting the QT interval. Clinically relevant effects on prolongation of the QTc-interval have not been observed in clinical studies of Onbrez Breezhaler at recommended therapeutic doses (see section 5.1).

Hypokalaemia

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

Hyperglycaemia

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

During clinical studies, clinically notable changes in blood glucose were generally more frequent by 1-2% on Onbrez Breezhaler at the recommended doses than on placebo. Onbrez Breezhaler has not been investigated in patients with not well controlled diabetes mellitus.

Excipients

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

Sympathomimetic medicinal products

Concomitant administration of other sympathomimetic medicinal products (alone or as part of combination therapy) may potentiate adverse reactions to Onbrez Breezhaler.

Onbrez Breezhaler should not be used in conjunction with other long-acting beta₂-adrenergic agonists or medicinal products containing long-acting beta₂-adrenergic agonists.

Hypokalaemic treatment

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

Beta-adrenergic blockers

Beta-adrenergic blockers and beta₂-adrenergic agonists may weaken or antagonise the effect of each other when administered concurrently. Therefore indacaterol should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution.

Metabolic and transporter based interactions

Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-glycoprotein (P-gp) raises the systemic exposure of indacaterol by up to two-fold. The magnitude of exposure increases due to interactions does not raise any safety concerns given the safety experience of treatment with Onbrez Breezhaler in clinical studies of up to one year at doses up to twice the maximum recommended therapeutic dose.

Indacaterol has not been shown to cause interactions with medicinal products administered concomitantly. In vitro investigations have indicated that indacaterol has negligible potential to cause metabolic interactions with medicinal products at the systemic exposure levels achieved in clinical practice.

Pregnancy

There are no data from the use of indacaterol in pregnant women available. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant exposures (see section 5.3). Like other beta₂-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle. Onbrez Breezhaler should only be used during pregnancy if the expected benefits outweigh the potential risks.

Breast-feeding

It is not known whether indacaterol/metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of indacaterol/metabolites in milk (see section 5.3). A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Onbrez Breezhaler therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

A decreased pregnancy rate has been observed in rats. Nevertheless, it is considered unlikely that indacaterol will affect reproductive or fertility performance in humans following inhalation of the maximum recommended dose (see section 5.3).

Onbrez Breezhaler has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions at the recommended doses were nasopharyngitis (14.3%), upper respiratory tract infection (14.2%), cough (8.2%), headache (3.7%) and muscle spasms (3.5%). These were in the vast majority mild or moderate and became less frequent if treatment was continued.

At the recommended doses, the adverse reaction profile of Onbrez Breezhaler in patients with COPD shows clinically insignificant systemic effects of beta₂-adrenergic stimulation. Mean heart rate changes were less than one beat per minute, and tachycardia was infrequent and reported at a similar rate as under placebo treatment. Relevant prolongations of QTcF were not detectable in comparison to placebo. The frequency of notable QTcF intervals [i.e. >450 ms (males) and >470 ms (females)] and reports of hypokalaemia were similar to placebo. The mean of the maximum changes in blood glucose were similar between Onbrez Breezhaler and placebo.

Tabulated summary of adverse reactions

The Onbrez Breezhaler Phase III clinical development programme involved patients with a clinical diagnosis of moderate to severe COPD. 4,764 patients were exposed to indacaterol up to one year at doses up to twice the maximum recommended dose. Of these patients, 2,611 were on treatment with 150 microgram once daily and 1,157 on treatment with 300 microgram once daily. Approximately 41% of patients had severe COPD. The mean age of patients was 64 years, with 48% of patients aged 65 years or older, and the majority (80%) was Caucasian.

Adverse reactions in Table 1 are listed according to MedDRA system organ class in the COPD safety database. Within each system organ class, adverse reactions are ranked by frequency in descending order according to the following convention: 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), not known (cannot be estimated from the available data).

Table 1. Adverse reactions:

¹ Reports of hypersensitivity have been received from post-approval marketing experience in association with the use of Onbrez Breezhaler. These were reported voluntarily from a population of uncertain size, and it is therefore not always possible to reliably estimate the frequency or establish a causal relationship to exposure to the medicinal product. Therefore the frequency was calculated from clinical trial experience.

At 600 microgram once-daily, the safety profile of Onbrez Breezhaler was overall similar to that of recommended doses. An additional adverse reaction was tremor (common).

Description of selected adverse reactions

In Phase III clinical studies, healthcare providers observed during clinic visits that on average 17-20% of patients experienced a sporadic cough that occurred usually within 15 seconds following inhalation and typically lasted for 5 seconds (about 10 seconds in current smokers). It was observed with a higher frequency in female than in male patients and in current smokers than in ex-smokers. This cough experienced post inhalation did not lead to any patient discontinuing from the studies at the recommended doses (cough is a symptom in COPD and only 8.2% of patients reported cough as an adverse event). There is no evidence that cough experienced post inhalation is associated with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy.

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.