Onbrez Breezhaler

Onbrez Breezhaler

indacaterol

Manufacturer:

Novartis

Distributor:

Zuellig
/
Four Star
Full Prescribing Info
Contents
Indacaterol maleate.
Description
The delivered dose (the dose that leaves the mouthpiece of the Onbrez Breezhaler inhaler) is equivalent to indacaterol 120 or 240 mcg, respectively. It also contains lactose monohydrate and gelatin as excipients.
Action
Pharmacotherapeutic Group: Long-acting β2-adrenergic agonist.
Pharmacology: Pharmacodynamics: Onbrez Breezhaler, administered once daily at doses of 150 and 300 mcg consistently provided clinically significant improvements in lung function (as measured by the forced expiratory volume in 1 sec, FEV1) over 24 hrs across a number of clinical pharmacodynamic and efficacy studies. There was a rapid onset of action within 5 min after inhalation, with an increase in FEV1 relative to baseline of 110-160 mL, comparable to the effect of the fast-acting β2-agonist salbutamol 200 mcg and statistically significantly faster compared to salmeterol/fluticasone 50/500 mcg. Mean peak improvements in FEV1 relative to baseline were 250-330 mL at steady state.
The bronchodilator effect did not depend on the time of dosing, morning or evening.
Onbrez Breezhaler was shown to reduce lung hyperinflation, resulting in increased inspiratory capacity during exercise and at rest, compared to placebo.
Effects on Cardiac Electrophysiology: A double-blind, placebo-controlled and active (moxifloxacin)-controlled study for 2 weeks in 404 healthy volunteers demonstrated maximum mean (90% confidence intervals) prolongations of the QTCF interval (in millisec) of 2.66 (0.55, 4.77) 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) following multiple doses of 150, 300 and 600 mcg, respectively. Therefore, this shows no concern for a pro-arrhythmic potential related to QT-interval prolongations at recommended therapeutic doses or at twice the maximum recommended dose. There was no evidence of a concentration-delta QTC relationship in the range of doses evaluated.
As demonstrated in 605 patients with chronic obstructive pulmonary disease (COPD) in a 26-week, double-blind, placebo-controlled phase III study, there was no clinically relevant difference in the development of arrhythmic events monitored over 24 hrs, at baseline and up to 3 times during the 26-week treatment period, between patients receiving recommended doses of Onbrez Breezhaler treatment and those patients who received placebo or treatment with tiotropium.
Clinical Efficacy and Safety: The clinical development programme included one 12-week, two 6-month (one of which was extended to 1 year to evaluate safety and tolerability) and one 1-year randomized, controlled studies in patients with a clinical diagnosis of COPD. These studies included measures of lung function and of health outcomes eg, dyspnoea, exacerbations and health-related quality of life.
Lung Function: Onbrez Breezhaler, administered once daily at doses of 150 and 300 mcg, showed clinically meaningful improvements in lung function. At the 12-week primary endpoint (24-hr trough FEV1), the 150 mcg dose resulted in a 130-180 mL increase compared to placebo (p<0.001) and a 60 mL increase compared to salmeterol 50 mcg twice daily (p<0.001). The 300 mcg dose resulted in a 170-180 mL increase compared to placebo (p<0.001) and a 100 mL increase compared to formoterol 12 mcg twice daily (p<0.001). Both doses resulted in an increase of 40-50 mL over open-label tiotropium 18 mcg once daily (150 mcg, p=0.004; 300 mcg, p=0.01). The 24-hr bronchodilator effect of Onbrez Breezhaler was maintained from the 1st dose throughout a 1-year treatment period with no evidence of loss in efficacy (tachyphylaxis).
Symptomatic Benefits: Both doses demonstrated statistically significant improvements in symptom relief over placebo for dyspnoea and health status [as evaluated by Transitional Dyspnoea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ), respectively]. The magnitude of response was generally greater than seen with active comparators (see table). In addition, patients treated with Onbrez Breezhaler required significantly less rescue medication, had more days when no rescue medication was needed compared to placebo and had a significantly improved percentage of days with no daytime symptoms.
Pooled efficacy analysis over 6 months treatment demonstrated that the rate of COPD exacerbations was statistically significantly lower than the placebo rate. Treatment comparison compared to placebo showed a ratio of rates of 0.68 [95% CI (0.47, 0.98); p-value 0.036] and 0.74 [95% CI (0.56, 0.96); p-value 0.026] for 150 and 300 mcg, respectively.
Limited treatment experience is available in individuals of African descent.

Click on icon to see table/diagram/image

Paediatric Population: The European Medicines Agency has waived the obligation to submit the results of studies with Onbrez Breezhaler in all subsets of the paediatric population in COPD (see Use in children under Precautions).
Mechanism of Action: The pharmacological effects of β2-adrenoceptor agonists are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3',5;-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol, a long-acting β2-adrenergic agonist, has >24-fold greater agonist activity at β2-receptors compared to β1-receptors and 20-fold greater agonist activity compared to β3-receptors.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonist at the human β2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the human heart, there are also β2-adrenergic receptors in the human heart comprising 10-50% of the total adrenergic receptors. The precise function of β2-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective β2-adrenergic agonists may have cardiac effects.
Pharmacokinetics: Indacaterol is a chiral molecule with R-configuration.
Pharmacokinetic data were obtained from a number of clinical studies, from healthy volunteers and COPD patients.
Absorption: The median time to reach peak serum concentrations of indacaterol was approximately 15 min after single or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose (150-600 mcg) in a dose proportional manner. Absolute bioavailability of indacaterol after an inhaled dose was on average 43%. Systemic exposure results from a composite of pulmonary and intestinal absorption.
Indacaterol serum concentrations increased with repeated once-daily administration. Steady state was achieved within 12-14 days. The mean accumulation ratio of indacaterol ie, AUC over the 24-hr dosing interval on day 14 compared to day 1, was in the range of 2.9-3.5 for once-daily inhaled doses between 150 and 600 mcg.
Distribution: After IV infusion the volume of distribution of indacaterol during the terminal elimination phase was 2557 L indicating an extensive distribution. The in vitro human serum and plasma protein-binding was 94.1-95.3% and 95.1-96.2%, respectively.
Biotransformation: After oral administration of radiolabelled indacaterol in a human absorption, distribution, metabolism, excretion (ADME) study, unchanged indacaterol was the main component in serum, accounting for about 1/3 of total drug-related AUC over 24 hrs. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C-dealkylated and N-dealkylated products were further metabolites identified.
In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolised indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6 and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.
Elimination: In clinical studies, which included urine collection, the amount of indacaterol excreted unchanged via urine was generally <2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 L/hr. When compared with the serum clearance of indacaterol of 23.3 L/hr, it is evident that renal clearance plays a minor role (about 2-5% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the faecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchanged parent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5-126 hrs. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing ranged from 40-52 hrs, which is consistent with the observed time-to-steady state of approximately 12-14 days.
Special Populations: A population pharmacokinetic analysis showed that there is no clinically relevant effect of age (adults up to 88 years), sex, weight (32-168 kg) or race on the pharmacokinetics of indacaterol. It did not suggest any difference between ethnic subgroups in this population.
Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein-binding differ between mild and moderate hepatic impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.
Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.
Toxicology: Preclinical Safety Data: Effects on the cardiovascular system attributable to the β2-agonistic properties of indacaterol included tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritancy of the nasal cavity and larynx were seen in rodents. All these findings occurred at exposures sufficiently in excess of those anticipated in humans.
Although indacaterol did not affect general reproductive performance in a rat fertility study, a decrease in the number of pregnant F1 offspring was observed in the peridevelopmental and post-developmental rat study at an exposure 14-fold higher than in humans treated with Onbrez Breezhaler. Indacaterol was not embryotoxic or teratogenic in rats or rabbits.
Genotoxicity studies did not reveal any mutagenic or clastogenic potential. Carcinogenicity was assessed in a 2-year rat study and a 6-month transgenic mouse study. Increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in rats were consistent with similar findings reported for other β2-adrenergic agonists. No evidence of carcinogenicity was seen in mice. Systemic exposures (AUC) in rats and mice at the no-observed adverse effect levels in these studies were at least 7- and 49-fold higher, respectively, than in humans treated with Onbrez Breezhaler once daily at a dose of 300 mcg.
Indications/Uses
For maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD.
Dosage/Direction for Use
Recommended Dose: Inhalation of the content of one 150-mcg cap once daily, using the Onbrez Breezhaler inhaler. The dosage should only be increased on medical advice.
The inhalation of the content of one 300-mcg cap once daily, using the Onbrez Breezhaler inhaler, has been shown to provide additional clinical benefit with regard to breathlessness, particularly for patients with severe COPD. The maximum dose is 300 mcg once daily.
Hepatic Impairment: No dose adjustment is required in patients with mild and moderate hepatic impairment. There are no data available for use of Onbrez Breezhaler in patients with severe hepatic impairment.
Renal Impairment: No dose adjustment is required for patients with renal impairment.
Elderly: Maximum plasma concentration and overall systemic exposure increase with age but no dose adjustment is required in elderly patients.
Administration: For inhalation use only. Onbrez Breezhaler capsules must not be swallowed.
Onbrez Breezhaler should be administered at the same time of the day each day. If a dose is missed, the next dose should be taken at the usual time the next day.
The Onbrez Breezhaler provided with each prescription should be used. Dispose each inhaler after 30 days of use.
Instructions for Handling and Use: Pull off the cap. Open Inhaler: Hold the base of the inhaler firmly and tilt the mouthpiece to open the inhaler.
Prepare Capsule: Immediately before use, with dry hands, remove one capsule from the blister.
Insert Capsule: Place the capsule into the capsule chamber. Never place a capsule directly into the mouthpiece.
Close the Inhaler: Close the inhaler until a "click" sound is heard.
Pierce the Capsule: Hold the inhaler upright with the mouthpiece pointing up. Pierce the capsule by firmly pressing together both side buttons at the same time. Do this only once. A "click" sound should be heard as the capsule is being pierced. Release the side buttons fully.
Breathe Out: Before placing the mouthpiece in the mouth, breathe out fully. Do not blow into the mouthpiece.
Inhale the Medicine: To breathe the medicine deeply into the airway, hold the inhaler, the side buttons should be facing left and right. Do not press the side buttons. Place the mouthpiece in the mouth and close the lips firmly around it. Breathe in rapidly but steadily and as deeply as the patient can.
Note: As the patient breathes in through the inhaler, the capsule spins around in the chamber and a whirring noise should be heard. The patient will experienced a sweet flavour as the medicine goes into the lungs.
Additional Information: Occasionally, very small pieces of the capsule can get past the screen and enter the mouth. If this happens, the patient may be able to feel these pieces on the tongue. It is not harmful if these pieces are swallowed or inhaled. The chances of the capsule shattering will be increased if the capsule is accidentally pierced more than once.
If a whirring noise is not heard, the capsule may be stuck in the capsule chamber. If this happens, open the inhaler and carefully loosen the capsule by tapping the base of the inhaler. Do not press the side buttons. Inhale the medicine again by repeating steps 8 and 9.
Hold Breath: After the patient has inhaled the medicine, hold the breath for at least 5-10 sec or as long as the patient comfortably can while taking the inhaler out of the mouth. Then breathe out. Open the inhaler to see if any powder is left in the capsule. If there is powder left in the capsule, close the inhaler and repeat steps 8-11. Most people are able to empty the capsule with 1 or 2 inhalations.
Additional Information: Some people may occasionally cough briefly soon after inhaling the medicine. But for as long as the capsule is empty, the full dose has been received.
After finished taking the Onbrez Breezhaler, open the mouthpiece again, and remove the empty capsule by tipping it out of the capsule chamber, and discard it. Close the inhaler and replace the cap. Do not store the capsules in the Onbrez Breezhaler inhaler.
Mark Daily Dose Tracker: On the inside of the pack, there is a daily dose tracker. Put a mark in today's box if it helps to remind when the next dose is due.
Overdosage
In COPD patients, single doses of 10 times the maximum recommended therapeutic dose were associated with a moderate increase in pulse rate, systolic blood pressure and QTc interval.
An overdose of indacaterol is likely to lead to exaggerated effects typical of β2-adrenergic stimulants ie, tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalaemia and hyperglycaemia.
Supportive and symptomatic treatment is indicated. In serious cases, patients should be hospitalised. Use of cardioselective β-blockers may be considered, but only under the supervision of a physician and with extreme caution since the use of β-adrenergic blockers may provoke bronchospasm.
Contraindications
Hypersensitivity to indacaterol maleate, lactose and to any of the other excipients of Onbrez Breezhaler.
Special Precautions
Asthma: Onbrez Breezhaler should not be used in asthma due to the absence of long-term outcome data in asthma with Onbrez Breezhaler.
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 instituted.
Deterioration of Disease: Onbrez Breezhaler is not indicated for treatment of acute episodes of bronchospasm ie, as a rescue therapy. In the event of deterioration of COPD during treatment with Onbrez Breezhaler, a re-evaluation of the patient and the COPD treatment regimen should be undertaken. An increase in the daily dose of Onbrez Breezhaler beyond the maximum dose of 300 mcg 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 β2-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 β2-adrenergic agonists.
Cardiovascular Effects: Like other β2-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, β-adrenergic agonists have been reported to produce ECG changes eg, flattening of the T wave and ST segment depression, although the clinical significance of these findings is unknown.
Clinically relevant effects on prolongation of the QTc-interval have not been observed in clinical studies of Onbrez Breezhaler at recommended therapeutic doses (see Pharmacology under Actions).
Hypokalaemia: β2-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 Interactions), which may increase the susceptibility to cardiac arrhythmias.
Hyperglycaemia: Inhalation of high doses of β2-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.
Effects on the Ability to Drive or Operate Machinery: Onbrez Breezhaler has no or negligible influence on the ability to drive and use machines.
Impairment of 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 Preclinical Safety Data under Toxicology under Actions).
Use In Pregnancy & Lactation
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 Preclinical Safety Data under Toxicology under Actions). Like other β2-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.
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 Preclinical Safety Data under Toxicology under Actions). A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Onbrez Breezhaler therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Adverse Reactions
Summary of the Safety Profile: The most common adverse reactions at the recommended doses were nasopharyngitis (9.1%), cough (6.8%), upper respiratory tract infection (6.2%) and headache (4.8%). These were in the vast majority mild or moderate and became less frequent if treatment was continued.
At the recommended doses, the adverse drug reaction profile of Onbrez Breezhaler in patients with COPD shows clinically insignificant systemic effects of β2-adrenergic stimulation. Mean heart rate changes were <1 beat/min, 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 [ie, >450 millisec (males) and >470 millisec (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. Two thousand one hundred fifty-four (2154) patients were exposed to indacaterol up to 1 year at doses up to twice the maximum recommended dose. Of these patients, 627 were on treatment with 150 mcg once daily and 853 on treatment with 300 mcg once daily. Approximately 40% of patients had severe COPD. The means age of patients was 63 years, with 47% of patients aged ≥65 years, and the majority (89%) was Caucasian.
Adverse reactions 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 (CIOMS III): Very common (≥1/10); common (≥1/100) to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Infections and Infestations: Common: Nasopharyngitis, upper respiratory infection, sinusitis.
Metabolism and Nutrition Disorders: Common: Diabetes mellitus and hyperglycaemia.
Nervous System Disorders: Common: Headache. Uncommon: Paraesthesia.
Cardiac Disorders: Common: Ischaemic heart disease. Uncommon: Atrial Fibrillation.
Respiratory, Thoracic and Mediastinal Disorders: Common: Cough, pharyngolaryngeal pain, rhinorrhoea, respiratory tract congestion.
Musculoskeletal and Connective Tissue Disorders: Common: Muscle spasm.
General Disorders and Administration Site Conditions: Common: Peripheral oedema. Uncommon: Non-cardiac chest pain.
At twice the maximum recommended dose, the safety profile of Onbrez Breezhaler was overall similar to that of recommended doses. Additional adverse reactions were tremor (common) and anaemia (uncommon).
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 sec following inhalation and typically lasted for 5 sec (about 10 sec 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 was generally well tolerated and did not lead to any patient discontinuing from the studies at the recommended doses (cough is a symptom in COPD and only 6.8% of patients overall 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.
Drug Interactions
Sympathomimetic Agents: Concomitant administration of other sympathomimetic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Onbrez Breezhaler.
Onbrez Breezhaler should not be used in conjunction with other long-acting β2-adrenergic agonists or medicinal products containing long-acting β2-adrenergic agonists.
Hypokalaemic Treatment: Concomitant treatment with methylxanthine derivatives, steroids or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of β2-adrenergic agonists (see Precautions).
Beta-Adrenergic Blockers: β-Adrenergic blockers may weaken or antagonise the effect of β2-adrenergic agonists. Therefore, Onbrez Breezhaler should not be given together with β-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Where required, cardioselective β-adrenergic blockers should be preferred, although they should be administered with caution.
Metabolic and Transporter-Based Drug Interactions: Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-gp raises the systemic exposure of indacaterol by up to 2-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 1 year at doses up to twice the maximum recommended therapeutic dose.
Indacaterol has not been shown to cause interactions with co-medications. In vitro investigations have indicated that indacaterol has negligible potential to cause metabolic interactions with medical products at the systemic exposure levels achieved in clinical practice.
ATC Classification
R03AC18 - indacaterol ; Belongs to the class of adrenergic inhalants, selective beta-2-adrenoreceptor agonists. Used in the treatment of obstructive airway diseases.
Presentation/Packing
Inhalation powd cap (+ inhaler device) 150 mcg (hard, clear, colourless capsules containing white powd with black product code "IDL 150" printed above and black company logo
Click on icon to see table/diagram/image
printed below a black bar) x 30's. 300 mcg (hard, clear, colourless capsules containing white powd with blue product code "IDL 300" printed above and blue company logo
Click on icon to see table/diagram/image
printed below a blue bar) x 30's.
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