Seebri Breezhaler

Glycopyrronium.

Each inhalation powder capsule contains glycopyrronium bromide 63 mcg equivalent to glycopyrronium 50 mcg .
It also contains the following excipients: Capsule fill: Lactose monohydrate and magnesium stearate. Capsule shell components: Hypromellose, purified water, carrageenan, potassium chloride and FDC yellow 6 (110 sunset yellow FCF).
The delivered dose (the dose that leaves the mouthpiece of Seebri Breezhaler inhaler) is equivalent to glycopyrronium 44 mcg.

Pharmacotherapeutic group: Anticholinergics. ATC code: R03BB06.
Pharmacology: Pharmacodynamics: Mechanism of Action: Seebri Breezhaler is an inhaled long-acting muscarinic receptor antagonist (anticholinergic) for once-daily maintenance bronchodilator treatment of chronic obstructive pulmonary disease (COPD). Parasympathetic nerves are the major bronchoconstrictive neural pathway in airways, and cholinergic tone is the key reversible component of airfow obstruction in COPD. Seebri Breezhaler works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells thereby dilating the airways.
Of the 5 known muscarinic receptor subtypes (M1-5), only subtypes M1-3 have a defined physiological function in the human lung. Glycopyrronium bromide is a high affinity muscarinic receptor antagonist of these 3 receptor subtypes. It demonstrated 4- to 5-fold selectivity for the human M3 and M1 receptors over the human M2 receptor in competition 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 drug concentrations in the lungs as reflected by the prolonged terminal elimination half-life (t_½) of glycopyrronium after inhalation via the Seebri Breezhaler inhaler in contrast to the half-life after IV administration (see Elimination in the following text). Lung pharmacokinetic data in rats following inhalation of glycopyrronium bromide provides further evidence for this.
Primary Pharmacodynamic Effects: Seebri Breezhaler provided consistently significant improvement in lung function (as measured by the forced expiratory volume in 1 sec, FEV₁) over 24 hrs in a number of clinical pharmacodynamic and efficacy trials.
In the pivotal studies there was a rapid onset of action within 5 min after inhalation of Seebri Breezhaler, with an increase in FEV₁ relative to baseline ranging from 0.091-0.094 L. During the 1st 4 hrs after drug administration, bronchodilation was significantly greater with Seebri Breezhaler than with the long-acting muscarinic antagonist tiotropium, the treatment difference ranged from 0.03-0.068 L. The bronchodilator effect of Seebri Breezhaler was sustained over 24 hrs. There was no evidence for tachyphylaxis to the bronchodilator effect after repeated dosing for up to 52 weeks.
Secondary Pharmacodynamic Effects: The effect on heart rate and QTc interval of glycopyrronium bromide 150 mcg (equivalent to glycopyrronium 120 mcg) administered IV was investigated in young healthy subjects. Peak exposures (C_max) about 50-fold higher than after inhalation of Seebri Breezhaler 50 mcg at steady-state were achieved and did not result in tachycardia or QT(c) prolongation. Negligible signs of bradycardia were observed [mean difference over 24 hr -2 beats per min (bpm) when compared to placebo], which is a known effect of low exposures to anticholinergic compounds in young healthy subjects. In a thorough QT study in 73 healthy volunteers, a single inhaled-dose of Seebri Breezhaler 352 mcg (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 hrs 2.8 bpm) when compared to placebo. No changes in heart rate or QT(c) interval were observed with Seebri Breezhaler 200 mcg in COPD patients.
Clinical Efficacy: Clinical studies: The Seebri Breezhaler Phase III clinical development program consisted of 2 key studies (a 6-month, placebo-controlled study and a 12-month placebo and active-controlled study) which enrolled 1888 patients with a clinical diagnosis of COPD, who were ≥40 years, had a smoking history of at least l0 packs/year, had a post-bronchodilator FEV₁ <80% and ≥30% of the predicted normal value and a post-bronchodilator FEV₁/FVC ratio of <70%.
Lung Function: In these studies, Seebri Breezhaler, administered at 50 mcg once-daily showed clinically meaningful improvements in lung function (as measured by the forced expiratory volume in 1 sec, FEV₁) over 24 hrs. At the 12-week primary endpoint (24-hr trough FEV₁), Seebri Breezhaler provided bronchodilation benefits of 0.108 L and 0.097 L compared to placebo (p<0.00l) for the 6- and 12-month study respectively. In the latter study, the improvement versus placebo for the open-label tiotropium 18 mcg once-daily arm was 0.083 L (p<0.001).
In both studies Seebri Breezhaler demonstrated a rapid onset of bronchodilator effect. In the 6-month study, the increase in FEV₁ was 0.093 L compared to placebo at 5 min, increasing to 0.144 L at 15 min after the 1st dose. In the 12-month study, the increase in FEV₁ was 0.087 L at 5 min and 0.143 L at 15 min after the 1st dose compared to placebo (p<0.001). In the 12-month study the increase in FEV₁ was 0.087 L at 5 min and 0.143 L at 15 min after the 1st dose compared to placebo (p<0.001). In the 12-month study, Seebri Breezhaler also produced statistically significant improvements in FEV₁ compared to tiotropium in the 1st 4 hrs after dosing on day 1 by 0.056 L (p>0.001) and at week 26 by 0.05 L (p<0.005). Numerically greater values for FEV₁ in the 1st 4 hrs after dosing, than tiotropium at week 12 (0.03 L) and week 52 (0.015 L).
In the pivotal studies there was a rapid onset of action within 5 min after inhalation of Seebri Breezhaler, with an increase in FEV₁ relative to baseline ranging from 0.091-0.094 L.
The improvements in mean trough FE/₁ observed at the primary endpoint (12 weeks) were maintained throughout treatment in both the 6- and 12-months studies. Mean trough FEV, was increased by 0.113 L at week 26 in the 6-month study and 0.108 L at week 52 in the 12-month study, compared to placebo. These data indicate that the 24-hr bronchodilator effect of Seebri Breezhaler was maintained from the 1st dose throughout a 1-year period.
In the 6-month study serial spirometry was performed on day 1 (see Figure 1), week 12 (see Figure 2) and week 26. In the 12 month study serial spirometry was performed on day 1 (see Figure 3), week 12 (see Figure 4) and week 52.
Serial spirometry data was used to calculate FEV₁ standardized (for time) area under the curve (AUC). In the 6-month study for FEV₁ AUC 0-24 hr Seebri Breezhaler provided a benefit of 0.133 L and 0.199 L compared to placebo at week 12 and week 26 respectively (p<0.001). In the 12-month study at week 12, Seebri Breezhaler provided a benefit of 0.106 L for FEV₁ AUC 0-24 hr (p<0.001) compared to placebo; for tiotropium, the treatment difference was 0.079 L compared to placebo (p=0.014). At week 52 in the 12-month study Seebri Breezhaler provided a benefit of 0.106 L for FEV₁ AUC 0-24 hr compared to placebo (p<0.001); for tiotropium, the treatment difference compared to placebo was 0.04 L (p=0.279).
The magnitude of the bronchodilator effect with Seebri Breezhaler 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 0.072 L in patients with the lowest degree of reversibility (<5%) and by 0.113 L in those patients with a higher degree of reversibility at baseline (≥5%) compared to placebo (both p<0.05). Similar findings were observed with patients receiving tiotropium. Following 12 weeks treatment with tiotropium, patients with the lowest degree of reversibility at baseline (<5%) were found to have an increase in trough FEV₁ of 0.059 L compared to placebo, while those patients with a higher degree of reversibility at baseline (≥5%) were found to have an increase in trough FEV₁ of 0.097 L compared to placebo. (See Figures 1-4.)


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In addition to demonstrating improvements in FEV₁, Seebri Breezhaler consistently improved forced vital capacity (FVC) and inspiratory capacity (IC) in the 2 pivotal studies. At week 12 Seebri Breezhaler was shown to increase mean trough FVC by 0.194 L and 0.183 L compared to placebo (p<0.001) in the 6- and 12-month studies respectively. Seebri Breezhaler improved trough IC at week 12 by 0.097 L and 0.129 L (p≤0.001) compared to placebo in the 6- and 12-month studies, respectively.
Symptomatic Benefit: Seebri Breezhaler administered at 50 mcg once-daily significantly reduced breathlessness as evaluated by the transitional dyspnea index (TDI). In a pooled analysis of the 6- and 12-month pivotal studies the percentage of patients responding with a clinically meaningful difference of ≥1 point improvement in the TDI focal score at week 26 was 58.4% for Seebri Breezhaler compared with 46.4% for patients receiving placebo and 53.4% for patients receiving tiotropium. The differences in responder rates were statistically signifcant for the comparison of Seebri Breezhaler to placebo (<0.001) and tiotropium to placebo (p=0.009). Seebri Breezhaler 50 mcg once-daily has also a significant effect on health status measured using the St. George's respiratory questionnaire (SGRQ). A pooled analysis of the 6- and 12-month pivotal studies found the percentage of patients responding with a clinically important improvement in the SGRQ total score (≤-4) at week 26 was 57.8% for Seebri Breezhaler compared with 47.6% for patients receiving placebo and 61% for patients receiving tiotropium. The differences in responder rates were statistically significant for the comparison of Seebri Breezhaler to placebo (<0.001) and tiotropium to placebo (p=0.004).
In a pooled analysis of the 6- and 12-month studies, Seebri Breezhaler 50 mcg once-daily significantly prolonged the time to 1st moderate or severe COPD exacerbation and reduced the rate of moderate or severe COPD exacerbations (moderate exacerbations were those requiring treatment with systemic corticosteroids and/or antibiotics, severe exacerbations those resulting in hospitalisation. The proportion of patients with moderate or severe COPD exacerbations in the 26-week pooled analysis was 19.8% for Seebri Breezhaler versus 27.2% for placebo and the estimated risk ratio for time to moderate or severe exacerbations was 0.64 [95% CI: 0.52, 0.799; p<0.001], suggesting a 36% risk reduction versus placebo, similarly the estimated risk ratio for time to 1st severe exacerbation leading to hospitalization was 0.39 [95% CI: 0.205, 0.728; p=0.003]. Over the 26-week pooled analysis the exacerbation rate was statistically significantly lower for patients treated with Seebri Breezhaler compared to those treated with placebo, the rate ratio being 0.66 [95% CI: 0.525, 0.841; p<0.001]. Seebri Breezhaler 50 mcg once-daily significantly reduced the use of rescue medication by 0.46 puffs/day (p=0.005) over 26 weeks and by 0.37 puffs/day (p=0.039) over 52 weeks compared to placebo for the 6- and 12-month studies respectively.
The effect of Seebri Breezhaler reducing dynamic hyperinflation and the associate improvements in exercise tolerance were investigated in a randomised, double-blind, placebo controlled trial in 108 patients with moderate to severe COPD. Seebri Breezhaler achieved its full effect of improving inspiratory capacity under exercise (0.23 L) and has statistically significant effects on exercise endurance of 43 sec (an increase of 10%) after the 1st dose. After 3 weeks of treatment Seebri Breezhaler improved exercise endurance time by 89 sec (an increase of 21%) and inspiratory capacity under exercise was increased by 0.2 L. 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 TDI.
Pharmacokinetics: Absorption: Following oral inhalation using the Seebri Breezhaler inhaler, glycopyrronium was rapidly absorbed and reached peak plasma levels at 5 min post-dose.
The absolute bioavailability of glycopyrromium inhaled via Seebri Breezhaler inhaler was estimated to be about 40%. About 90% of systemic exposure following inhalation is due to lung absorption and 10% is due to gastrointestinal absorption. The absolute bioavailability of orally administered glycopyrronium was estimated to be about 5%.
Following repeated once-daily inhalation in patients with COPD, pharmacokinetic steady-state of glycopyrronium was reached within 1 week of treatment. The steady-state mean peak and trough plasma concentrations of glycopyrronium for a 50 mcg once-daily dosing regimen were 166 pg/mL and 8 pg/mL, respectively. With once-daily doses of 100 mcg and 200 mcg, steady-state exposure to glycopyrronium (AUC over the dosing interval) was about 1.4- to 1.7-fold higher than after the 1st dose. Urinary excretion data at steady-state compared to the 1st dose suggest that systemic accumulation is independent of dose in the dose range of 25-200 mcg.
Distribution: After IV dosing, the steady-state volume of distribution (Vss) of glycopyrronium was 83 L and the volume of distribution in the terminal phase (V_z) was 376 L. The apparent volume of distribution in the terminal phase following inhalation (V_z/F) was 7310 L, which reflects the much slower elimination after inhalation. The in vitro human plasma protein binding of glycopyrronium was 38-41% at concentrations of 1-10 ng/mL. These concentrations were at least 6-fold higher than the steady-state mean peak level achieved in plasma for a 50 mcg once-daily dosing regimen.
Biotransformation/Metabolism: In vitro metabolism studies showed consistent metabolic pathways for glycopyrronium bromide between animals and humans. No human specific metabolites were found. 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 vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. The hydrolysis to M9 is likely to be catalyzed by members from the cholinesterase family.
After inhalation, systemic exposure to M9 was on average in the same order of magnitude as the exposure to the parent drug. Since in vitro studies did not show lung metabolism and M9 was of minor importance in the circulation (about 4% of parent drug C_max and AUC) after IV administration, it is assumed that M9 is formed from the swallowed dose fraction of orally inhaled glycopyrronium bromide by presystemic hydrolysis and/or via first-pass metabolism. After inhalation as well as IV administration, only minimal amounts of M9 were found in the urine (ie, ≤0.5% of dose). Glucuronide and/or sulfate conjugates of glycopyrronium were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.
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 OCT 1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrronium bromide for any of the cytochrome P450 isoenzymes tested as well as for UGT1A1 and the transporters MDR1 and MRP2.
Elimination: After IV administration of [³H]-labelled glycopyrronium bromide to humans, the mean urinary excretion of radioactivity in 48 hr amounted to 85% of the dose. A further 5% of the dose was found in the bile. Thus, mass balance was almost complete.
Renal elimination of parent drug accounts for about 60-70% of total clearance of systemically available glycopyrronium whereas nonrenal clearance processes account for about 30-40%. Biliary clearance contributes to the nonrenal clearance, but the majority of nonrenal clearance is thought to be due to metabolism.
Following inhalation of single and repeated once-daily doses between 50 mcg and 200 mcg glycopyrronium by healthy volunteers and patients with COPD mean renal clearance of glycopyrronium was in the range of 17.4 L/hr and 24.4 L/hr. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to 20% of the dose was found in urine as parent drug.
Glycopyrronium plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life (t_½) was much longer after inhalation (33-57 hrs) than after IV (6.2 hrs) and oral (2.8 hrs) administration. The elimination pattern suggests a sustained lung absorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 hr after inhalation.
Linearity/Nonlinearity: In COPD patients' systemic exposure as well as total urinary excretion of glycopyrronium at pharmacokinetic steady-state increased about dose-proportionally over the dose range of 50-200 mcg.
Special Populations: A population PK analysis of data in COPD patients identified body weight and age as factors contributing to inter-patient variability in systemic exposure. Seebri Breezhaler 50 mcg 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.
Patients with Hepatic Impairment: Clinical studies in patients with hepatic impairment have not been conducted. Glycopyrronium is cleared predominantly from the systemic circulation by renal excretion (see Elimination under Pharmacokinetics). Impairment of the hepatic metabolism of glycopyrronium is not thought to result in a clinically relevant increase of systemic exposure.
Patients with Renal Impairment: Renal impairment has an impact on the systemic exposure to glycopyrronium bromide. A moderate mean increase in total systemic exposure (AUC last) 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. Using a population PK analysis, it was concluded that in COPD patients with mild and moderate renal impairment (estimated glomerular filtration rate eGFR ≥230 mL/min/1.73 m^₂) Seebri Breezhaler can be used at the recommended dose.
Ethnicity: There were no major differences in total systemic exposure (AUC) between Japanese and Caucasian subjects following inhalation of glycopyrronium bromide. Insufficient PK data is available for other ethnicities or races.
Toxicology: Nonclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.
The effects seen during repeated-dose inhalation toxicity studies were attributable to exacerbations of the expected pharmacological action of glycopyrronium bromide or mild local irritation. These included mild to moderate increases in heart rate in dogs and a number of reversible changes in rat and dogs associated with reduced secretions from the salivary, lacrimal and Harderian glands and pharynx. Lens opacities observed during chronic studies in rats have been described for other muscarinic antagonists and are considered to be species specific changes with limited relevance for therapeutic use in patients. Findings in the respiratory tract of rats included degenerative/regenerative changes and inflammation in the nasal cavity and larynx that are consistent with mild local irritation. Minimal epithelial changes in the lung at the bronchioloalveolar junction were also observed in rats and are regarded as a mild adaptive response. All these findings were observed at exposures considered to be sufficiently in excess of the maximum human exposure and therefore indicate limited relevance during clinical use.
Genotoxicity: Studies did not reveal any mutagenic or clastogenic potential for glycopyrronium bromide.
Carcinogenicity: Studies in transgenic mice using oral administration and in rats using inhalation administration, revealed no evidence of carcinogenicity at systemic exposures (AUC) of approximately 53-fold higher in mice and 75-fold higher in rats than the maximum recommended dose of 50 mcg once-daily for humans.
Reproductive Toxicity: Published data for glycopyrronium bromide do not indicate any reproductive toxicity issues. Seebri Breezhaler was not teratogenic in rats or rabbits following inhalation administration. Reproduction studies in rats and other data in animals did not indicate a concern regarding fertility in either males or females or pre- and post-natal development. Glycopyrronium bromide and its metabolites did not significantly cross the placental barrier of pregnant mice, rabbits and dogs. Glycopyrronium bromide (including its metabolites) was excreted into the milk of lactating rats and reached up to 10-fold higher concentrations in the milk than in the blood of the dam.

As once-daily maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD).

Adult: Recommended Dose: Once-daily inhalation using Seebri Breezhaler inhaler.
Renal Impairment: Seebri 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 Pharmacology under Actions and Precautions).
Hepatic Impairment: No specific studies have been conducted in patients with hepatic impairment. Seebri Breezhaler is predominantly cleared by renal excretion and therefore no major increase in exposure is expected in patients with hepatic impairment.
Elderly ≥75 years: Seebri Breezhaler can be used at the recommended dose in elderly patients.
Missed Dose: If a dose is missed, the next dose should be taken as soon as possible.
Maximum Dose: One dose/day
Administration: Seebri Breezhaler must be administered only by the oral inhalation route and only using the Seebri Breezhaler inhaler. Seebri Breezhaler capsules must not be swallowed (see Overdosage). Seebri Breezhaler is recommended to be administered once-daily at the same time of the day each day.

In COPD patients, repeated orally inhaled administration of Seebri Breezhaler at total doses of 100 and 200 mcg once-daily for 28 days were well tolerated. Acute intoxication by inadvertent oral ingestion of Seebri Breezhaler capsules is unlikely due to the low oral bioavailability (about 5%).
Peak plasma levels and total systemic exposure following IV administration of 150 mcg glycopyrronium bromide (equivalent to glycopyrronium 120 mcg) in healthy volunteers were respectively about 50-fold and 6-fold higher than the peak and total systemic exposure at steady-state achieved with the recommended dose (50 mcg once-daily) of Seebri Breezhaler and were well tolerated.

Hypersensitivity to glycopyrronium or to any of the excipients of Seebri Breezhaler.
Should not be used in patients <18 years of age. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Seebri Breezhaler is a once-daily long-term maintenance treatment and is not indicated for the initial treatment of acute episodes of bronchospasm, ie. as a rescue therapy.
Paradoxical Bronchospasm: As with other inhalation therapy, administration of Seebri Breezhaler may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, Seebri Breezhaler should be discontinued immediately and alternative therapy instituted.
Anticholinergic Effect: Like other anticholinergic drugs, Seebri Breezhaler should be used with caution in patients with narrow-angle glaucoma or urinary retention. Patients should be advised about 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 Impairment: A moderate mean increase in total system exposure (AUC last) 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. For patients with severe renal impairment (estimated glomeruiar filtration rate <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 Pharmacology under Actions). These patients should be monitored closely for potential adverse drug reactions.
Patients with A History of Cardiovascular Disease: Patients with unstable ischaemic heart disease, eg, 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.
Use in pregnancy & lactation: Women of Childbearing Potential: There are no special recommendations for women of childbearing potential.
Fertility: Reproduction studies and other data in animals did not indicate a concern regarding fertility in either males or females (see Nonclinical Safety Data under Toxicology under Actions).
Pregnancy: No clinical data on exposed pregnancies in COPD patients are available. Seebri Breezhaler was not teratogenic in rats or rabbits following inhalational administration (see Nonclinical Safety Data under Toxicology under Actions). In human parturients undergoing caesarean section, 86 min after a single IM injection of 0.006 mg/kg glycopyrronium bromide, umbilical plasma concentrations were low. As there is no adequate experience in pregnant women, Seebri Breezhaler should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.
Breastfeeding: It is not known whether glycopyrronium bromide passes into human breast milk. However, glycopyrronium bromide (including its metabolites) was excreted into the milk of lactating rats. The use of Seebri Breezhaler by breastfeeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant (see Nonclinical Safety Data under Toxicology under Actions).

Women of Childbearing Potential: There are no special recommendations for women of childbearing potential.
Fertility: Reproduction studies and other data in animals did not indicate a concern regarding fertility in either males or females (see Nonclinical Safety Data under Toxicology under Actions).
Pregnancy: No clinical data on exposed pregnancies in COPD patients are available. Seebri Breezhaler was not teratogenic in rats or rabbits following inhalational administration (see Nonclinical Safety Data under Toxicology under Actions). In human parturients undergoing caesarean section, 86 min after a single IM injection of 0.006 mg/kg glycopyrronium bromide, umbilical plasma concentrations were low. As there is no adequate experience in pregnant women, Seebri Breezhaler should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.
Breastfeeding: It is not known whether glycopyrronium bromide passes into human breast milk. However, glycopyrronium bromide (including its metabolites) was excreted into the milk of lactating rats. The use of Seebri Breezhaler by breastfeeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant (see Nonclinical Safety Data under Toxicology under Actions).

Summary Of The Safety Profile: The safety and tolerability of Seebri Breezhaler has been explored at the recommended dose of 50 mcg once-daily in 1353 COPD patients. Of these, 842 patients have been treated for at least 26 weeks, and 351 patients for at least 52 weeks. The safety profile is characterized by symptoms related to the anticholinergic effect including dry mouth while other gastrointestinal effects and signs of urinary retention were infrequent.
Adverse drug reactions related to local tolerability included throat irritation, nasopharyngitis, rhinitis and sinusitis. At the recommended dose Seebri Breezhaler is devoid of effects on blood pressure or heart rate.
Adverse drug reactions reported during the 1st 6 months of 2 pooled pivotal Phase III trials of 6- and 12-months duration are listed by MedDRA system organ class (see table). Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions 1st. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100). (See table.)


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In the 12-month study, the following additional events were more frequent on Seebri Breezhaler than on placebo: Nasopharyngitis (9% versus 5.6%), vomiting (1.3% versus 0.7%), musculoskeletal pain (1.1% versus 0.7%), neck pain (1.3% versus 0.7%), diabetes mellitus (0.8% versus 0%).
Description of Selected Adverse Drug Reactions: The most common anticholinergic adverse event was dry mouth. The majority of the reports of dry mouth were suspected to be drug related and of mild degree, none was severe. Rash was uncommon and generally mild.
Special Populations: In elderly patients >75 years of age the frequencies of urinary tract infection and headache were higher on Seebri Breezhaler than on placebo with 3% versus 1.5% and 2.3% versus 0%, respectively.

The co-administration of Seebri Breezhaler with inhaled anticholinergic-containing drugs has not been studied and is therefore, like for other anticholinergics, not recommended. Concomitant administration of Seebri Breezhaler and orally inhaled indacaterol, β₂-adrenergic agonist; under steady-state conditions of both drugs did not affect the pharmacokinetics of either drug.
In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport which is thought to contribute to the renal excretion of glycopyrronium, increased total exposure (AUC) to glycopyrronium by 22% and decreased renal clearance by 23%. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when Seebri Breezhaler is co-administered with cimetidine or other inhibitors of the organic cation transport.
In vitro studies showed that Seebri Breezhaler is not likely to inhibit or induce the metabolism of other drugs, nor processes involving drug transporters. Metabolism in which multiple enzymes are involved, plays a secondary role in the elimination of glycopyrronium (see Biotransformation/Metabolism and Elimination under Actions). Inhibition or induction of metabolism of glycopyrronium is unlikely to result in a relevant change of systemic exposure to the drug.

Do not store above 30°C. Protect from moisture.
Shelf-Life: 18 months.

Antiasthmatic & COPD Preparations

R03BB06 - glycopyrronium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.

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