- 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
- Legal category
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 the inhalation of the content of one capsule once daily using the Seebri Breezhaler inhaler.Seebri Breezhaler is recommended to be administered, at the same time of the day each day. If a dose is missed, the next dose should be taken as soon as possible. Patients should be instructed not to take more than one dose in a day.
Elderly populationSeebri Breezhaler can be used at the recommended dose in elderly patients (75 years of age and older) (see section 4.8).
Renal impairmentSeebri Breezhaler can be used at the recommended dose in patients with mild to moderate renal impairment. In patients with severe renal impairment or end-stage renal disease requiring dialysis Seebri Breezhaler should be used only if the expected benefit outweighs the potential risk (see sections 4.4 and 5.2).
Hepatic impairmentNo studies have been conducted in patients with hepatic impairment. Glycopyrronium is predominantly cleared by renal excretion and therefore no major increase in exposure is expected in patients with hepatic impairment.
Paediatric populationThere is no relevant use of Seebri Breezhaler in the paediatric population (under 18 years) in the indication COPD.
Method of administrationFor inhalation use only.The capsules must be administered only using the Seebri Breezhaler inhaler (see section 6.6).The capsules must not be swallowed.Patients should be instructed on how to administer the product correctly. Patients who do not experience improvement in breathing should be asked if they are swallowing the medicine rather than inhaling it.For instructions on use of the medicinal product before administration, see section 6.6.
Not for acute useSeebri Breezhaler is a once-daily, long-term maintenance treatment and is not indicated for the initial treatment of acute episodes of bronchospasm, i.e. as a rescue therapy.
HypersensitivityImmediate hypersensitivity reactions have been reported after administration of Seebri Breezhaler. 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, Seebri Breezhaler should be discontinued immediately and alternative therapy instituted.
Paradoxical bronchospasmIn clinical studies with Seebri Breezhaler, paradoxical bronchospasm was not observed. However, paradoxical bronchospasm has been observed with other inhalation therapy and can be life-threatening. If this occurs, Seebri Breezhaler should be discontinued immediately and alternative therapy instituted.
Anticholinergic effectSeebri Breezhaler should be used with caution in patients with narrow-angle glaucoma or urinary retention.Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stop using Seebri Breezhaler and to contact their doctor immediately should any of these signs or symptoms develop.
Patients with severe renal impairmentA moderate mean increase in total system exposure (AUClast) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment and up to 2.2-fold in subjects with severe renal impairment and end-stage renal disease. In 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, Seebri Breezhaler should be used only if the expected benefit outweighs the potential risk (see section 5.2). These patients should be monitored closely for potential adverse reactions.
Patients with a history of cardiovascular diseasePatients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc (Fridericia method) was prolonged (>450 ms for males or >470 ms for females) were excluded from the clinical trials, and therefore the experience in these patient groups is limited. Seebri Breezhaler should be used with caution in these patient groups.
ExcipientsPatients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
PregnancyThere are no data from the use of Seebri Breezhaler in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Glycopyrronium should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus.
Breast-feedingIt is unknown whether glycopyrronium bromide is excreted in human milk. However, glycopyrronium bromide (including its metabolites) was excreted in the milk of lactating rats (see section 5.3). The use of glycopyrronium by breast-feeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant (see section 5.3).
FertilityReproduction studies and other data in animals do not indicate a concern regarding fertility in either males or females (see section 5.3).
Summary of the safety profileThe most common anticholinergic adverse reaction was dry mouth (2.4%). The majority of the reports of dry mouth were suspected to be related to the medicinal product and were mild, with none being severe.The safety profile is further characterised by other symptoms related to the anticholinergic effects, including signs of urinary retention, which were uncommon. Gastrointestinal effects including gastroenteritis and dyspepsia were also observed. Adverse reactions related to local tolerability included throat irritation, nasopharyngitis, rhinitis and sinusitis.
Tabulated summary of adverse reactionsAdverse reactions reported during the first six months of two pooled pivotal Phase III trials of 6 and 12 months duration are listed by MedDRA system organ class (Table 1). Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on 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 reported in the pooled 6-month database
|Adverse reactions||Frequency category|
|Infections and infestations|
|Immune system disorders|
|Metabolism and nutrition disorders|
|Nervous system disorders|
|Respiratory, thoracic and mediastinal disorders|
|Paradoxical bronchospasm2)||Not known|
|Skin and subcutaneous tissue disorders|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||Uncommon|
|Musculoskeletal chest pain||Uncommon|
|Renal and urinary disorders|
|Urinary tract infection3)||Common|
|General disorders and administration site conditions|
1) More frequent for glycopyrronium than placebo in the 12 months database only.2) Reports have been received from post-approval marketing experience in association with the use of Seebri 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 drug exposure. Therefore the frequency was calculated from clinical trial experience.
3) Seen more frequently for glycopyrronium than placebo in elderly >75 years only.
Description of selected adverse reactionsIn the pooled 6-month database the frequency of dry mouth was 2.2% versus 1.1%, of insomnia 1.0% versus 0.8%, and of gastroenteritis 1.4% versus 0.9%, for Seebri Breezhaler and placebo respectively.Dry mouth was reported mainly during the first 4 weeks of treatment with a median duration of four weeks in the majority of patients. However in 40% of cases symptoms continued for the entire 6-month period. No new cases of dry mouth were reported in months 7-12.
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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Mechanism of actionSeebri Breezhaler is an inhaled long-acting muscarinic receptor antagonist (anticholinergic) for once-daily maintenance bronchodilator treatment of COPD. Parasympathetic nerves are the major bronchoconstrictive neural pathway in airways, and cholinergic tone is the key reversible component of airflow obstruction in COPD. Glycopyrronium works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, thereby dilating the airways.Glycopyrronium bromide is a high affinity muscarinic receptor antagonist. A greater than 4-fold selectivity for the human M3 receptors over the human M2 receptor has been demonstrated using radioligand binding studies. It has a rapid onset of action as evidenced by observed receptor association/dissociation kinetic parameters and the onset of action after inhalation in clinical studies.The long duration of action can be partly attributed to sustained concentrations of active substance in the lung as reflected by the prolonged terminal elimination half-life of glycopyrronium after inhalation via the Seebri Breezhaler inhaler in contrast to the half life after intravenous administration (see section 5.2).
Pharmacodynamic effectsThe clinical Phase III development programme included two phase III studies: a 6-month placebo-controlled study and a 12-month placebo and active-controlled (open label tiotropium 18 micrograms once daily) study, both in patients with clinical diagnosis of moderate to severe COPD.
Effects on lung functionSeebri Breezhaler 44 micrograms once daily provided consistently statistically significant improvement in lung function (forced expiratory volume in one second, FEV1, forced vital capacity, FVC, and inspiratory capacity, IC) in a number of clinical studies. In phase III studies, bronchodilator effects were seen within 5 minutes after the first dose and were maintained over the 24-hour dosing interval from the first dose. There was no attenuation of the bronchodilator effect over time in the 6- and 12-month studies. The magnitude of the effect was dependent on the degree of reversibility of airflow limitation at baseline (tested by administration of a short-acting muscarinic antagonist bronchodilator): Patients with the lowest degree of reversibility at baseline (<5%) generally exhibited a lower bronchodilator response than patients with a higher degree of reversibility at baseline (≥5%). At 12 weeks (primary endpoint), Seebri Breezhaler increased trough FEV1 by 72 ml in patients with the lowest degree of reversibility (<5%) and by 113 ml in those patients with a higher degree of reversibility at baseline (≥5%) compared to placebo (both p<0.05).In the 6-month study, Seebri Breezhaler increased FEV1 after the first dose with an improvement of 93 ml within 5 minutes and 144 ml within 15 minutes of dosing, compared to placebo (both p<0.001). In the 12-month study, the improvements were 87 ml at 5 minutes and 143 ml at 15 minutes (both p<0.001). In the 12-month study, Seebri Breezhaler produced statistically significant improvements in FEV1 compared to tiotropium in the first 4 hours after dosing on day 1 and at week 26, and numerically greater values for FEV1 in the first 4 hours after dosing than tiotropium at week 12 and week 52.The values for FEV1 at the end of the dosing interval (24 h post dose) were similar between the first dose and those seen after 1 year of dosing. At 12 weeks (primary endpoint), Seebri Breezhaler increased trough FEV1 by 108 ml in the 6-month study and by 97 ml in the 12-month study compared to placebo (both p<0.001). In the 12-month study, the improvement versus placebo for tiotropium was 83 ml (p<0.001).
Symptomatic outcomesSeebri Breezhaler administered at 44 micrograms once daily statistically significantly reduced breathlessness as evaluated by the Transitional Dyspnoea Index (TDI). In a pooled analysis of the 6- and 12-month pivotal studies a statistically significantly higher percentage of patients receiving Seebri Breezhaler responded with a 1 point or greater improvement in the TDI focal score at week 26 compared to placebo (58.4% and 46.4% respectively, p<0.001). These findings were similar to those seen in patients receiving tiotropium, 53.4% of whom responded with 1 point or greater improvement (p=0.009 compared to placebo).Seebri Breezhaler once daily has also shown a statistically significant effect on health-related quality of life measured using the St. George's Respiratory Questionnaire (SGRQ). A pooled analysis of the 6- and 12-month pivotal studies found a statistically significantly higher percentage of patients receiving Seebri Breezhaler responded with a 4 point or greater improvement in SGRQ compared to placebo at week 26 (57.8% and 47.6% respectively, p<0.001). For patients receiving tiotropium, 61.0% responded with a 4 point or greater improvement in SGRQ (p=0.004 compared to placebo).
COPD exacerbations reductionCOPD exacerbation data was collected in the 6- and 12month pivotal studies. In both studies, the percentage of patients experiencing a moderate or severe exacerbation (defined as requiring treatment with systemic corticosteroids and/or antibiotics or hospitalisation) was reduced. In the 6-month study, the percentage of patients experiencing a moderate or severe exacerbation was 17.5% for Seebri Breezhaler and 24.2% for placebo (Hazard ratio: 0.69, p=0.023), and in the 12-month study it was 32.8% for Seebri Breezhaler and 40.2% for placebo (Hazard ratio: 0.66, p=0.001). In a pooled analysis of the first 6 months of treatment in the 6- and 12-month studies, compared to placebo Seebri Breezhaler statistically significantly prolonged time to first moderate or severe exacerbation and reduced the rate of moderate or severe COPD exacerbations (0.53 exacerbations/year versus 0.77 exacerbations /year, p<0.001). The pooled analysis also showed fewer patients treated with Seebri Breezhaler than with placebo experienced an exacerbation requiring hospitalisation (1.7% versus 4.2%, p=0.003).
Other effectsSeebri Breezhaler once daily statistically significantly reduced the use of rescue medication (salbutamol) by 0.46 puffs per day (p=0.005) over 26 weeks and by 0.37 puffs per day (p=0.039) over 52 weeks, compared to placebo for the 6- and 12-month studies, respectively.In a 3-week study where exercise tolerance was tested via cycle ergometer at submaximal (80%) workload (submaximal exercise tolerance test), Seebri Breezhaler, dosed in the morning, reduced dynamic hyperinflation and improved the length of time exercise could be maintained from the first dose onwards. On the first day of treatment inspiratory capacity under exercise was improved by 230 ml and exercise endurance time was improved by 43 seconds (an increase of 10%) compared to placebo. After three weeks of treatment the improvement in inspiratory capacity with Seebri Breezhaler was similar to the first day (200 ml), exercise endurance time however had increased by 89 seconds (an increase of 21%) compared to placebo. Seebri Breezhaler was found to decrease dyspnoea and leg discomfort when exercising as measured using Borg scales. Seebri Breezhaler also reduced dyspnoea at rest measured using the Transitional Dyspnoea Index.
Secondary pharmacodynamic effectsNo change in mean heart rate or QTc interval was observed with Seebri Breezhaler in doses up to 176 micrograms in COPD patients. In a thorough QT study in 73 healthy volunteers, a single inhaled dose of glycopyrronium 352 micrograms (8 times the therapeutic dose) did not prolong the QTc interval and slightly reduced heart rate (maximal effect -5.9 bpm; average effect over 24 hours -2.8 bpm) when compared to placebo. The effect on heart rate and QTc interval of 150 micrograms glycopyrronium bromide (equivalent to 120 micrograms glycopyrronium) administered intravenously was investigated in young healthy subjects. Peak exposures (Cmax) about 50-fold higher than after inhalation of glycopyrronium 44 micrograms at steady state were achieved and did not result in tachycardia or QTc prolongation. A slight reduction in heart rate (mean difference over 24 h -2 bpm when compared to placebo), which is a known effect of low exposures to anticholinergic compounds in young healthy subjects, was observed.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Seebri Breezhaler in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use).
AbsorptionFollowing oral inhalation using the Seebri Breezhaler inhaler, glycopyrronium was rapidly absorbed and reached peak plasma levels at 5 minutes post dose.The absolute bioavailability of glycopyrromium inhaled via Seebri Breezhaler was estimated to be about 45% of the delivered dose. About 90% of systemic exposure following inhalation is due to lung absorption and 10% is due to gastrointestinal absorption.In patients with COPD, pharmacokinetic steady-state of glycopyrronium was reached within one week of the start of treatment. The steady-state mean peak and trough plasma concentrations of glycopyrronium for a 44 micrograms once-daily dosing regimen were 166 picograms/ml and 8 picograms/ml, respectively. Steady-state exposure to glycopyrronium (AUC over the 24-hour dosing interval) was about 1.4- to 1.7-fold higher than after the first dose.
DistributionAfter intravenous dosing, the steady-state volume of distribution of glycopyrronium was 83 litres and the volume of distribution in the terminal phase was 376 litres. The apparent volume of distribution in the terminal phase following inhalation was almost 20-fold larger, which reflects the much slower elimination after inhalation. The in vitro human plasma protein binding of glycopyrronium was 38% to 41% at concentrations of 1 to 10 nanograms/ml.
BiotransformationIn vitro metabolism studies showed consistent metabolic pathways for glycopyrronium bromide between animals and humans. Hydroxylation resulting in a variety of mono-and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9) were seen. In vivo, M9 is formed from the swallowed dose fraction of inhaled glycopyrronium bromide. Glucuronide and/or sulfate conjugates of glycopyrronium were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.Multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. Inhibition or induction of the metabolism of glycopyrronium is unlikely to result in a relevant change of systemic exposure to the active substance.In vitro inhibition studies demonstrated that glycopyrronium bromide has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrronium bromide for cytochrome P450 isoenzymes, or for UGT1A1 and the transporters MDR1 and MRP2.
EliminationAfter intravenous administration of [3H]-labelled glycopyrronium bromide to humans, the mean urinary excretion of radioactivity in 48 hours amounted to 85% of the dose. A further 5% of the dose was found in the bile.Renal elimination of parent drug accounts for about 60 to 70% of total clearance of systemically available glycopyrronium whereas non-renal clearance processes account for about 30 to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.Mean renal clearance of glycopyrronium following inhalation was in the range of 17.4 and 24.4 litres/h. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to 23% of the delivered dose was found in urine as parent drug.Glycopyrronium plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life was much longer after inhalation (33 to 57 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration. The elimination pattern suggests sustained lung absorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 hours after inhalation.
Linearity/non-linearityIn COPD patients both systemic exposure and total urinary excretion of glycopyrronium at pharmacokinetic steady state increased about dose-proportionally over the dose range of 44 to 176 micrograms.
Special populationsA population pharmacokinetic analysis of data in COPD patients identified body weight and age as factors contributing to inter-patient variability in systemic exposure. Seebri Breezhaler 44 micrograms once daily can be safely used in all age and body weight groups.Gender, smoking status and baseline FEV1 had no apparent effect on systemic exposure.There were no major differences in total systemic exposure (AUC) between Japanese and Caucasian subjects following inhalation of glycopyrronium bromide. Insufficient pharmacokinetic data is available for other ethnicities or races.
Patients with hepatic impairmentClinical studies have not been conducted in patients with hepatic impairment. Glycopyrronium is cleared predominantly from the systemic circulation by renal excretion. Impairment of the hepatic metabolism of glycopyrronium is not thought to result in a clinically relevant increase of systemic exposure.
Patients with renal impairmentRenal impairment has an impact on the systemic exposure to glycopyrronium bromide. A moderate mean increase in total systemic exposure (AUClast) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment and up to 2.2-fold in subjects with severe renal impairment and end-stage renal disease. In COPD patients with mild and moderate renal impairment (estimated glomerular filtration rate, eGFR ≥30 ml/min/1.73 m2) Seebri Breezhaler can be used at the recommended dose. In patients with severe renal impairment (eGFR <30 ml/min/1.73 m2), including those with end-stage renal disease requiring dialysis, Seebri Breezhaler should only be used in the expected benefit outweighs the potential risk (see section 4.4).
Capsule contentLactose monohydrateMagnesium stearate
Instructions for handling and use
|How to use your inhaler|
|Pull off the cap.|
|Open inhaler:Hold the base of the inhaler firmly and tilt the mouthpiece. This opens the inhaler.|
|Prepare capsule:Separate one of the blisters from the blister card by tearing along the perforation. Take one blister and peel away the protective backing to expose the capsule. Do not push capsule through foil.|
|Remove a capsule:Capsules should always be stored in the blister and only removed immediately before use. With dry hands, remove capsule from the blister. Do not swallow the capsule.|
|Insert capsule:Place the capsule into the capsule chamber. Never place a capsule directly into the mouthpiece.|
|Close the inhaler:Close the inhaler until you hear a click.|
|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.• You should hear a click as the capsule is being pierced.|
|Release the side buttons fully.|
|Breathe out:Before placing the mouthpiece in your mouth, breathe out fully. Do not blow into the mouthpiece.|
|Inhale the medicine:To breathe the medicine deeply into your airways: • Hold the inhaler as shown in the picture. The side buttons should be facing left and right. Do not press the side buttons. • Place the mouthpiece in your mouth and close your lips firmly around it. • Breathe in rapidly but steadily, as deeply as you can. Do not press the side buttons.|
|Note:As you breathe in through the inhaler, the capsule spins around in the chamber and you should hear a whirring noise. You will experience a sweet flavour as the medicine goes into your lungs. If you do not hear a whirring noise: 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 9 and 10.|
|Hold breath:After you have inhaled the medicine:• Hold your breath for at least 5-10 seconds or as long as you comfortably can while taking the inhaler out of your 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. • Repeat steps 9 to 12. Most people are able to empty the capsule with one or two inhalations. Additional informationSome people occasionally cough briefly soon after inhaling a medicine. If you do, don't worry. As long as the capsule is empty, you have received enough of your medicine.|
|After you have finished taking your daily dose of Seebri Breezhaler: • Open the mouthpiece again, and remove the empty capsule by tipping it out of the capsule chamber. Put the empty capsule in your household waste. • Close the inhaler and replace the cap. Do not store the capsules in the Seebri Breezhaler inhaler.|
Novartis Pharmaceuticals UK Ltd
Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR
+44 (0)1276 698 449
+44 (0)1276 692 255
+44 (0)1276 698 370
+44 (0)845 741 9442