Indacaterol

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 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 indacaterol at recommended therapeutic doses.

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

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

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 indacaterol in clinical studies of up to one year at doses up to twice the maximum recommended therapeutic dose.

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.

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.

Although no clinically relevant effect on the cardiovascular system is usually seen after the administration of indacaterol 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.

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. Like other beta₂-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle. Indacaterol should only be used during pregnancy if the expected benefits outweigh the potential risks.

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. 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 indacaterol 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.

Indacaterol 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 indacaterol 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 indacaterol and placebo.

Tabulated summary of adverse reactions

The indacaterol 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 the table below 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).

¹ Reports of hypersensitivity have been received from post-approval marketing experience in association with the use of indacaterol. 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 indacaterol 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.