- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
PosologyThe recommended dose is one inhalation of 322 µg aclidinium twice daily.If a dose is missed the next dose should be taken as soon as possible. However, if it is nearly time for the next dose, the missed dose should be skipped.
Elderly populationNo dose adjustments are required for elderly patients (see section 5.2).
Renal impairmentNo dose adjustments are required for patients with renal impairment (see section 5.2).
Hepatic impairmentNo dose adjustments are required for patients with hepatic impairment (see section 5.2).
Paediatric populationThere is no relevant use of Eklira Genuair in children and adolescents (under 18 years of age) in the indication of COPD.
Method of administrationFor inhalation use.Patients should be instructed on how to administer the product correctly.Instructions for use:Becoming familiar with Eklira Genuair:Remove the Genuair inhaler from the pouch and become familiar with its components.
How to use Eklira Genuair
|SummaryTo use your Genuair inhaler there are 2 steps you need to perform after removing the cap:Step 1 - Press and RELEASE the green button and breathe out completely, away from the inhaler.Step 2 - Place your lips tightly around the mouthpiece and inhale STRONGLY and DEEPLY through the inhaler.After inhalation, remember to replace the protective cap.|
Getting Started• Before first use, tear the sealed pouch along the notch and remove the Genuair inhaler.• When you are about to take your dose of medicinal product, remove the protective cap by lightly squeezing the arrows marked on each side and pulling outwards (see image 1).• Look to see that nothing is blocking the mouthpiece.• Hold the Genuair inhaler horizontally with the mouthpiece towards you and the green button facing straight up (see image 2).STEP 1: PRESS the green button all the way down and then RELEASE it (see images 3 and 4).
DO NOT CONTINUE TO HOLD THE GREEN BUTTON DOWN.
Stop and Check: Make sure dose is ready for inhalation• Make sure the coloured control window has changed to green (see image 5).• The green control window confirms that your medicinal product is ready for inhalation.IF THE COLOURED CONTROL WINDOW STAYS RED, PLEASE REPEAT PRESS AND RELEASE ACTIONS (SEE STEP 1).• Before bringing the inhaler to your mouth, breathe out completely. Do not breathe out into the inhaler.STEP 2: Put your lips tightly around the mouthpiece of the Genuair inhaler and inhale STRONGLY and DEEPLY through the mouthpiece (see image 6).This strong, deep breath pulls the medicinal product through the inhaler into your lungs.• While you breathe in you will hear a CLICK which signals that you are using the Genuair inhaler correctly.• Keep breathing in even after you have heard the inhaler CLICK to be sure you get the full dose.• Remove the Genuair inhaler from your mouth and hold your breath for as long as is comfortable, then breathe out slowly through your nose.Note: Some patients may experience a mild sweet or slightly bitter taste, depending on the patient, when inhaling the medicinal product. Do not take an extra dose if you do not taste anything after inhaling.
Stop and Check: Make sure you have inhaled correctly• Make sure the control window has turned to red (see image 7). This confirms that you have inhaled your full dose correctly.
IF THE COLOURED CONTROL WINDOW IS STILL GREEN, PLEASE REPEAT INHALING STRONGLY AND DEEPLY THROUGH THE MOUTHPIECE (SEE STEP 2).• If the window still does not change to red, you may have forgotten to release the green button before inhaling or may not have inhaled correctly. If that happens, try again.Make sure you have RELEASED the green button and take a STRONG deep breath in through the mouthpiece.Note: If you are unable to inhale correctly after several attempts, consult your doctor.• Once the window has turned red, replace the protective cap by pressing it back onto the mouthpiece (see image 8).
When should you get a new Genuair inhaler?• The Genuair inhaler is equipped with a dose indicator to show you approximately how many doses are left in the inhaler. The dose indicator moves down slowly, displaying intervals of 10 (60, 50, 40, 30, 20, 10, 0) (see image A). Every Genuair inhaler will deliver at least 60 doses.• When a red striped band appears in the dose indicator (see image A), this means you are nearing your last dose and you should obtain a new Genuair inhaler.Note: If your Genuair inhaler appears to be damaged or if you lose the cap, your inhaler should be replaced. You DO NOT NEED to clean your Genuair inhaler. However, if you wish to clean it you should do so by wiping the outside of the mouthpiece with a dry tissue or paper towel. NEVER use water to clean the Genuair inhaler, as this may damage your medicine.
How do you know that your Genuair inhaler is empty?• When 0 (zero) appears in the middle of the dose indicator, you should continue using any doses remaining in the Genuair inhaler.• When the last dose has been prepared for inhalation, the green button will not return to its full upper position, but will be locked in a middle position (see image B). Even though the green button is locked, your last dose may still be inhaled. After that, the Genuair inhaler cannot be used again and you should start using a new Genuair inhaler.
Asthma:Eklira Genuair should not be used in asthma; clinical trials of aclidinium bromide in asthma have not been conducted.
Paradoxical bronchospasm:As with other inhalation therapies, administration of Eklira Genuair may cause paradoxical bronchospasm. If this occurs, treatment with Eklira Genuair should be stopped and other treatments considered.
Deterioration of disease:Aclidinium bromide is a maintenance bronchodilator and should not be used for the relief of acute episodes of bronchospasm, i.e. as a rescue therapy. In the event of a change in COPD intensity while the patient is being treated with aclidinium bromide so that the patient considers additional rescue medication is required, a re-evaluation of the patient and the patients' treatment regimen should be conducted.
Cardiovascular effects:Cardiovascular safety profile is characterized by the anticholinergic effects. Eklira Genuair should be used with caution in patients with a myocardial infarction during the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV as per the New York Heart Association. Such patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action.
Anticholinergic activity:Dry mouth, which has been observed with anticholinergic treatment, may in the long term be associated with dental caries.Consistent with its anticholinergic activity, aclidinium bromide should be used with caution in patients with symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma (even though direct contact of the product with the eyes is very unlikely).Excipients:Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
PregnancyThere are no data available on the use of aclidinium bromide in pregnant women.Studies in animals have shown fetotoxicity only at dose levels much higher than the maximum human exposure to aclidinium bromide (see section 5.3). Aclidinium bromide should only be used during pregnancy if the expected benefits outweigh the potential risks.
Breast-feedingIt is unknown whether aclidinium bromide and/or its metabolites are excreted in human milk. As animal studies have shown excretion of small amounts of aclidinium bromide and/or metabolites into milk, a decision must be made whether to discontinue breast-feeding or to discontinue therapy with aclidinium bromide taking into account the benefit of breast-feeding for the child and the benefit of long-term aclidinium bromide therapy to the woman.
FertilityStudies in rats have shown slight reductions in fertility only at dose levels much higher than the maximum human exposure to aclidinium bromide (see section 5.3). It is considered unlikely that aclidinium bromide administered at the recommended dose will affect fertility in humans.
Summary of the safety profileThe most frequently reported adverse reactions with Eklira Genuair were headache (6.6%) and nasopharyngitis (5.5%).
Tabulated summary of adverse reactionsThe frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse reactions (i.e. events attributed to Eklira Genuair) observed with Eklira Genuair 322 µg (636 patients) in the pooled analysis of one 6-month and two 3-month randomised, placebo-controlled clinical trials.The frequency of adverse reactions is defined using 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) and not known (cannot be estimated from available data).
|System organ class||Preferred term||Frequency|
|Infections and infestations||Sinusitis||Common|
|Immune system disorders||Hypersensitivity||Rare|
|Nervous system disorders||Headache||Common|
|Eye disorders||Blurred vision||Uncommon|
|Respiratory, thoracic and mediastinal disorders||Cough||Common|
|Skin and subcutaneous tissue disorders||Rash||Uncommon|
|Renal and urinary disorders||Urinary retention||Uncommon|
Reporting of suspected adverse reactionsReporting 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 (see details below).
United KingdomYellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
IrelandIMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.imb.ie, e-mail: firstname.lastname@example.org.
Pharmacodynamic effectsClinical efficacy studies showed that Eklira Genuair provided clinically meaningful improvements in lung function (as measured by the forced expiratory volume in 1 second [FEV1]) over 12 hours following morning and evening administration, which were evident within 30 minutes of the first dose (increases from baseline of 124-133 mL). Maximal bronchodilation was achieved within 1-3 hours after dosing with mean peak improvements in FEV1 relative to baseline of 227-268 mL at steady-state.
Cardiac electrophysiologyNo effects on QT interval (corrected using either the Fridericia or Bazett method or individually-corrected) were observed when aclidinium bromide (200 µg or 800 µg) was administered once daily for 3 days to healthy subjects in a thorough QT study.In addition, no clinically significant effects of Eklira Genuair on cardiac rhythm were observed on 24‑hour Holter monitoring after 3 months treatment of 336 patients (of whom 164 received Eklira Genuair 322 µg twice daily).
Clinical EfficacyThe Eklira Genuair Phase III clinical development programme included 269 patients treated with Eklira Genuair 322 µg twice daily in one 6-month randomised, placebo-controlled study and 190 patients treated with Eklira Genuair 322 µg twice daily in one 3-month randomised, placebo-controlled study. Efficacy was assessed by measures of lung function and symptomatic outcomes such as breathlessness, disease-specific health status, use of rescue medication and occurrence of exacerbations. In the long-term safety studies, Eklira Genuair was associated with bronchodilatory efficacy when administered over a 1-year treatment period.
BronchodilationIn the 6‑month study, patients receiving Eklira Genuair 322 µg twice daily experienced a clinically meaningful improvement in their lung function (as measured by FEV1). Maximal bronchodilatory effects were evident from day one and were maintained over the 6-month treatment period. After 6 months treatment, the mean improvement in morning pre-dose (trough) FEV1 compared to placebo was 128 mL (95% CI=85‑170; p<0.0001).Similar observations were made with Eklira Genuair in the 3 month study.
Disease-Specific Health Status and Symptomatic BenefitsEklira Genuair provided clinically meaningful improvements in breathlessness (assessed using the Transition Dyspnoea Index [TDI]) and disease-specific health status (assessed using the St. George's Respiratory Questionnaire [SGRQ]). The Table below shows symptom relief obtained after 6 months treatment with Eklira Genuair.
|Variable||Treatment||Improvement over placebo||p-value|
|Percentage of Patients who achieved MCIDa||56.9||45.5||1.68-foldc increase in likelihood||0.004|
|Mean Change from baseline||1.9||0.9||1.0 unit||<0.001|
|Percentage of Patients who achieved MCIDb||57.3||41.0||1.87-foldc increase in likelihood||<0.001|
|Mean Change from baseline||-7.4||-2.8||- 4.6 units||<0.0001|
Exercise toleranceIn a 3-week crossover, randomised, placebo-controlled clinical study Eklira Genuair was associated with a statistically significant improvement in exercise endurance time in comparison to placebo of 58 seconds (95% CI=9-108; p=0.021; pre-treatment value: 486 seconds). Eklira Genuair statistically significantly reduced lung hyperinflation at rest (functional residual capacity [FRC]=0.197 L [95% CI=0.321, 0.072; p=0.002]; residual volume [RV]=0.238 L [95% CI=0.396, 0.079; p=0.004]) and also improved trough inspiratory capacity (by 0.078 L; 95% CI=0.01, 0.145; p=0.025) and reduced dyspnoea during exercise (Borg scale) (by 0.63 Borg units; 95% CI=1.11, 0.14; p=0.012).
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Eklira Genuair in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use).
AbsorptionAclidinium bromide is rapidly absorbed from the lung, achieving maximum plasma concentrations within 5 minutes of inhalation in healthy subjects, and normally within the first 15 minutes in COPD patients. The fraction of the inhaled dose that reaches the systemic circulation as unchanged aclidinium is very low at less than 5%.Peak plasma concentrations achieved after dry powder inhalation by COPD patients of single doses of 400 µg aclidinium bromide were approximately 80 pg/mL. Steady-state plasma levels were attained within seven days of twice daily dosing and considering the short half life, steady-state may be reached soon after the first dose. No accumulation on repeat dosing was observed at steady-state.
DistributionWhole lung deposition of inhaled aclidinium bromide via the Genuair inhaler averaged approximately 30% of the metered dose.The plasma protein binding of aclidinium bromide determined in vitro most likely corresponded to the protein binding of the metabolites due to the rapid hydrolysis of aclidinium bromide in plasma; plasma protein binding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The main plasma protein that binds aclidinium bromide is albumin.
BiotransformationAclidinium bromide is rapidly and extensively hydrolysed to its pharmacologically inactive alcohol- and carboxylic acid-derivatives. The hydrolysis occurs both chemically (non-enzymatically) and enzymatically by esterases, butyrylcholinesterase being the main human esterase involved in the hydrolysis. Plasma levels of the acid metabolite are approximately 100-fold greater than those of the alcohol metabolite and the unchanged active substance following inhalation. The low absolute bioavailability of inhaled aclidinium bromide (<5%) is because aclidinium bromide undergoes extensive systemic and pre-systemic hydrolysis whether deposited in the lung or swallowed.Biotransformation via CYP450 enzymes plays a minor role in the total metabolic clearance of aclidinium bromide.In vitro studies have shown that aclidinium bromide at the therapeutic dose or its metabolites do not inhibit or induce any of the cytochrome P450 (CYP450) enzymes and do not inhibit esterases (carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro studies have shown that aclidinium bromide or the metabolites of aclidinium bromide are not substrates or inhibitors of P‑glycoprotein.
EliminationThe terminal elimination half-life of aclidinium bromide is approximately 2 to 3 hours.Following intravenous administration of 400 µg radiolabelled aclidinium bromide to healthy subjects, approximately 1% of the dose was excreted as unchanged aclidinium bromide in the urine. Up to 65% of the dose was eliminated as metabolites in the urine and up to 33% as metabolites in the faeces.Following inhalation of 200 µg and 400 µg of aclidinium bromide by healthy subjects or COPD patients, the urinary excretion of unchanged aclidinium was very low at about 0.1% of the administered dose, indicating that renal clearance plays a minor role in the total aclidinium clearance from plasma.
Linearity/non-linearityAclidinium bromide demonstrated kinetic linearity and a time-independent pharmacokinetic behaviour in the therapeutic range.
Pharmacokinetic/pharmacodynamic relationshipBecause aclidinium bromide acts locally in the lungs and is quickly broken down in plasma there is no direct relationship between pharmacokinetics and pharmacodynamics.
Elderly patientsThe pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPD appear to be similar in patients aged 4059 years and in patients aged ≥70 years. Therefore, no dose adjustment is required for elderly COPD patients.
Hepatically-impaired patientsNo studies have been performed on hepatically-impaired patients. As aclidinium bromide is metabolised mainly by chemical and enzymatic cleavage in the plasma, hepatic dysfunction is very unlikely to alter its systemic exposure. No dose adjustment is required for hepatically-impaired COPD patients.
Renally-impaired patientsNo significant pharmacokinetic differences were observed between subjects with normal renal function and subjects with renal impairment. Therefore, no dose adjustment and no additional monitoring are required for renally-impaired COPD patients.
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