Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics incl. triple combinations with corticosteroids.
ATC code: R03AL12
This medicinal product is a combination of indacaterol, a long-acting beta2-adrenergic agonist (LABA), glycopyrronium, a long-acting muscarinic receptor antagonist (LAMA) and mometasone furoate, an inhaled synthetic corticosteroid (ICS).
The pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in part attributable to increased cyclic-3', 5'-adenosine monophosphate (cyclic AMP) levels, which cause relaxation of bronchial smooth muscle.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonist at the human beta2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the human heart, there are also beta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors.
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. 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 by 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 of glycopyrronium after inhalation via the inhaler in contrast to the half-life after intravenous administration (see section 5.2).
Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory properties. In vitro, mometasone furoate inhibits the release of leukotrienes from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of leukotriene production and of the production of the Th2 cytokines IL-4 and IL-5 from human CD4+ T-cells.
The pharmacodynamic response profile of this medicinal product is characterised by rapid onset of action within 5 minutes after dosing and sustained effect over the whole 24-hour dosing interval.
The pharmacodynamic response profile is further characterised by increased mean peak forced expiratory volume in the first second (FEV1) of 172 ml following indacaterol/glycopyrronium/mometasone furoate 114 mcg/46 mcg/136 mcg once daily compared to salmeterol/fluticasone 50 mcg/500 mcg twice daily.
No tachyphylaxis to the lung function benefits of Zimbus Breezhaler was observed over time.
The effect of this medicinal product on the QTc interval has not been evaluated in a thorough QT (TQT) study. For mometasone furoate, no QTc prolonging properties are known.
The safety and efficacy of Zimbus Breezhaler in adult patients with persistent asthma was evaluated in the phase III randomised, double-blind study (IRIDIUM). The IRIDIUM study was a 52-week study evaluating Zimbus Breezhaler 114 mcg/46 mcg/68 mcg once daily (N=620) and 114 mcg/46 mcg/136 mcg once daily (N=619) compared to indacaterol/mometasone furoate 125 mcg/127.5 mcg once daily (N=617) and 125 mcg/260 mcg once daily (N=618), respectively. A third active control arm included subjects treated with salmeterol/fluticasone propionate 50 mcg/500 mcg twice daily (N=618). All subjects were required to have symptomatic asthma (ACQ-7 score ≥1.5) and were on asthma maintenance therapy using a medium or high dose inhaled synthetic corticosteroid (ICS) and LABA combination therapy for at least 3 months prior to study entry. The mean age was 52.2 years. At screening, 99.9% of patients reported a history of exacerbation in the past year. At study entry, the most common asthma medications reported were medium dose of ICS in combination with a LABA (62.6%) and high dose of ICS in combination with a LABA (36.7%).
The primary objective of the study was to demonstrate superiority of either Zimbus Breezhaler 114 mcg/46 mcg/68 mcg once daily over indacaterol/mometasone furoate 125 mcg/127.5 mcg once daily or Zimbus Breezhaler 114 mcg/46 mcg/136 mcg once daily over indacaterol/mometasone furoate 125 mcg/260 mcg once daily in terms of trough FEV1 at week 26.
Zimbus Breezhaler 114 mcg/46 mcg/136 mcg once daily demonstrated statistically significant improvements in trough FEV1 at week 26 compared to indacaterol/mometasone furoate at corresponding dose. Clinically meaningful improvements in lung function (change from baseline trough FEV1 at week 26, morning and evening peak expiratory flow) were also observed compared to salmeterol/fluticasone propionate 50 mcg/500 mcg twice daily. Findings at week 52 were consistent with week 26 (see Table 2).
All treatment groups showed clinically relevant improvements from baseline in ACQ-7 at week 26, however no statistically significant differences between groups were observed. The mean change from baseline in ACQ-7 at week 26 (key secondary endpoint) and week 52 was around -1 for all treatment groups. The ACQ-7 responder rates (defined as a change decrease in score of ≥0.5) at different time points are described in Table 2.
Exacerbations were a secondary endpoint (not part of confirmatory testing strategy). Zimbus Breezhaler 114 mcg/46 mcg/136 mcg once daily demonstrated a reduction in the annual rate of exacerbations compared to salmeterol/fluticasone propionate 50 mcg/500 mcg twice daily and indacaterol/mometasone furoate 125 mcg/260 mcg once daily (see Table 2).
Results for the most clinically relevant endpoints are described in Table 2.
Table 2. Results of primary and secondary endpoints in IRIDIUM study at weeks 26 and 52:
| Endpoint | Time point/Duration | Zimbus Breezhaler1 vs IND/MF2 | Zimbus Breezhaler1 vs SAL/FP3 |
|---|---|---|---|
| Lung function | |||
| Trough FEV14 | |||
| Treatment difference P value (95% CI) | Week 26 (Primary endpoint) | 65 ml <0,001 (31, 99) | 119 ml <0,001 (85, 154) |
| Week 52 | 86 ml <0,001 (51, 120) | 145 ml <0,001 (111, 180) | |
| Mean morning peak expiratory flow (PEF) | |||
| Treatment difference (95% CI) | Week 52* | 18,7 l/min (13,4, 24,1) | 34,8 l/min (29,5, 40,1) |
| Mean evening peak expiratory flow (PEF) | |||
| Treatment difference (95% CI) | Week 52* | 17,5 l/min (12,3, 22,8) | 29,5 l/min (24,2, 34,7) |
| Symptoms | |||
| ΆACQ responders (percentage of patients achieving minimal clinical important difference (MCID) from baseline with ACQ ≥0.5) | |||
| Percentage | Week 4 | 66% vs 63% | 66% vs 53% |
| Odds ratio (95% CI) | 1,21 (0,94, 1,54) | 1,72 (1,35, 2,20) | |
| Percentage | Week 12 | 68% vs 67% | 68% vs 61% |
| Odds ratio (95% CI) | 1,11 (0,86, 1,42) | 1,35 (1,05, 1,73) | |
| Percentage | Week 26 | 71% vs 74% | 71% vs 67% |
| Odds ratio (95% CI) | 0,92 (0,70, 1,20) | 1,21 (0,93, 1,57) | |
| Percentage | Week 52 | 79% vs 78% | 79% vs 73% |
| Odds ratio (95% CI) | 1,10 (0,83, 1,47) | 1,41 (1,06, 1,86) | |
| Annualised rate of asthma exacerbations | |||
| Moderate or severe exacerbations | |||
| AR | Week 52 | 0,46 vs 0,54 | 0,46 vs 0,72 |
| RR** (95% CI) | Week 52 | 0,85 (0,68, 1,04) | 0,64 (0,52, 0,78) |
| Severe exacerbations | |||
| AR | Week 52 | 0,26 vs 0,33 | 0,26 vs 0,45 |
| RR** (95% CI) | Week 52 | 0,78 (0,61, 1,00) | 0,58 (0,45, 0,73) |
* Mean value for the treatment duration.
** RR <1.00 favours indacaterol/glycopyrronium/mometasone furoate.
1 Zimbus Breezhaler 114 mcg/46 mcg/136 mcg od.
2 IND/MF: indacaterol/mometasone furoate high dose: 125 mcg/260 mcg od. Mometasone furoate 136 mcg in Zimbus Breezhaler is comparable to mometasone furoate 260 mcg in indacaterol/mometasone furoate.
3 SAL/FP: salmeterol/fluticasone propionate high dose: 50 mcg/500 mcg bid (content dose).
4 Trough FEV1: the mean of the two FEV1 values measured at 23 hours 15 min and 23 hours 45 min after the evening dose.
Primary endpoint (trough FEV1 at week 26) and key secondary endpoint (ACQ-7 score at week 26) were part of confirmatory testing strategy and thus controlled for multiplicity. All other endpoints were not part of confirmatory testing strategy.
RR = rate ratio, AR = annualised rate
od = once daily, bid = twice daily
A randomised, partially-blinded, active-treatment-controlled, non-inferiority study (ARGON) comparing Zimbus Breezhaler 114 mcg/46 mcg/136 mcg once daily (N=476) and 114 mcg/46 mcg/68 mcg once daily (N=474) to the concurrent administration of salmeterol/fluticasone propionate 50 mcg/500 mcg twice daily + tiotropium 5 mcg once daily (N=475) over 24 weeks of treatment was conducted.
Zimbus Breezhaler demonstrated non-inferiority to salmeterol/fluticasone + tiotropium for the primary endpoint (change from baseline for Asthma Quality of Life Questionnaire [AQLQ-S]), in previously symptomatic patients on ICS and LABA therapy with a difference of 0.073 (one-sided lower 97.5% confidence limit [CL]: -0.027).
The European Medicines Agency has deferred the obligation to submit the results of studies with indacaterol/glycopyrronium/mometasone furoate in one or more subsets of the paediatric population in asthma (see section 4.2 for information on paediatric use).
Following inhalation of Zimbus Breezhaler, the median time to reach peak plasma concentrations of indacaterol, glycopyrronium and mometasone furoate was approximately 15 minutes, 5 minutes and 1 hour, respectively.
Based on the in vitro performance data, the dose of each of the monotherapy components delivered to the lung is expected to be similar for the indacaterol/glycopyrronium/mometasone furoate combination and the monotherapy products. Steady-state plasma exposure to indacaterol, glycopyrronium and mometasone furoate after inhalation of the combination was similar to the systemic exposure after inhalation of indacaterol maleate, glycopyrronium or mometasone furoate as monotherapy products.
Following inhalation of the combination, the absolute bioavailability was estimated to be about 45% for indacaterol, 40% for glycopyrronium and less than 10% for mometasone furoate.
Indacaterol concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-h dosing interval on day 14 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 60 and 480 mcg (delivered dose). Systemic exposure results from a composite of pulmonary and gastrointestinal absorption; about 75% of systemic exposure was from pulmonary absorption and about 25% from gastrointestinal absorption.
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%.
Mometasone furoate concentrations increased with repeated once-daily administration via the Breezhaler inhaler. Steady state was achieved after 12 days. The mean accumulation ratio of mometasone furoate, i.e. AUC over the 24-h dosing interval on day 14 compared to day 1, was in the range of 1.28 to 1.40 for once-daily inhaled doses between 68 and 136 mcg as part of the indacaterol/glycopyrronium/mometasone furoate combination.
Following oral administration of mometasone furoate, the absolute oral systemic bioavailability of mometasone furoate was estimated to be very low (<2%).
After intravenous infusion the volume of distribution (Vz) of indacaterol was 2361 to 2557 litres, indicating an extensive distribution. The in vitro human serum and plasma protein binding were 94.1 to 95.3% and 95.1 to 96.2%, respectively.
After intravenous dosing, the steady-state volume of distribution (Vss) of glycopyrronium was 83 litres and the volume of distribution in the terminal phase (Vz) was 376 litres. The apparent volume of distribution in the terminal phase following inhalation (Vz/F) was 7,310 litres, 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 ng/ml. These concentrations were at least 6-fold higher than the steady-state mean peak levels achieved in plasma for a 44 mcg once-daily dosing regimen.
After intravenous bolus administration, the Vd is 332 litres. The in vitro protein binding for mometasone furoate is high, 98% to 99% in concentration range of 5 to 500 ng/ml.
After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. 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, an N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.
In vitro investigations indicated that UGT1A1 was 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.
In vitro the UGT1A1 isoform is a major contributor to the metabolic clearance of indacaterol. However, as shown in a clinical study in populations with different UGT1A1 genotypes, systemic exposure to indacaterol is not significantly affected by the UGT1A1-genotype.
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 catalysed by members of 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 Cmax and AUC) after intravenous administration, it is assumed that M9 is formed from the swallowed dose fraction of orally inhaled glycopyrronium bromide by pre-systemic hydrolysis and/or via first-pass metabolism. After inhalation as well as after intravenous administration, only minimal amounts of M9 were found in the urine (i.e. ≤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 OATP1B1, OATP1B3, OAT1, OAT3, OCT1 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.
The portion of an inhaled mometasone furoate dose that is swallowed and absorbed in the gastrointestinal tract undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. In human liver microsomes, mometasone furoate is metabolised by CYP3A4.
In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 litres/hour. Compared with the serum clearance of indacaterol of 18.8 to 23.3 litres/hour, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study in which 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 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing, ranged from 40 to 52 hours, which is consistent with the observed time to steady state of approximately 12 to 14 days.
After 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. Thus, mass balance was almost complete.
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 was in the range of 17.4 and 24.4 litres/hour. 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 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 a sustained lung absorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 h after inhalation.
After intravenous bolus administration, mometasone furoate has a terminal elimination T½ of approximately 4.5 hours. A radiolabelled, orally inhaled dose is excreted mainly in the faeces (74%) and to a lesser extent in the urine (8%).
Concomitant administration of orally inhaled indacaterol, glycopyrronium and mometasone furoate under steady-state conditions did not affect the pharmacokinetics of any of the active substances.
A population pharmacokinetic analysis in patients with asthma after inhalation of Zimbus Breezhaler indicated no significant effect of age, gender, body weight, smoking status, baseline estimated glomerular filtration rate (eGFR) and FEV1 at baseline on the systemic exposure to indacaterol, glycopyrronium or mometasone furoate.
The effect of renal impairment on the pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate has not been evaluated in dedicated studies with Zimbus Breezhaler. In a population pharmacokinetic analysis, estimated glomerular filtration rate (eGFR) was not a statistically significant covariate for systemic exposure of indacaterol, glycopyrronium and mometasone furoate following administration of Zimbus Breezhaler in patients with asthma.
Due to the very low contribution of the urinary pathway to the total body elimination of indacaterol and mometasone furoate, the effects of renal impairment on their systemic exposure have not been investigated (see sections 4.2 and 4.4).
Renal impairment has an impact on the systemic exposure to glycopyrronium administered as a monotherapy. 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. Based on a population pharmacokinetic analysis of glycopyrronium in asthma patients following Zimbus Breezhaler administration, AUC0-24h increased by 27% or decreased by 19% for patients with an absolute GFR of 58 or 143 ml/min, respectively, compared to a patient with an absolute GFR of 93 ml/min. Based on a population pharmacokinetic analysis of glycopyrronium in chronic obstructive pulmonary disease patients with mild and moderate renal impairment (eGFR ≥30 ml/min/1.73 m²), glycopyrronium can be used at the recommended dose.
The effect of hepatic impairment on the pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate has not been evaluated in subjects with hepatic impairment following administration of Zimbus Breezhaler. However, studies have been conducted with the monotherapy components indacaterol and mometasone furoate (see section 4.2).
Indacaterol:
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.
Glycopyrronium:
Clinical studies in patients with hepatic impairment have not been conducted. 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 in systemic exposure.
Mometasone furoate:
A study evaluating the administration of a single inhaled dose of 400 mcg mometasone furoate by dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/ml). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels (assay lower limit of quantification was 50 pcg/ml) were few.
There were no major differences in total systemic exposure (AUC) for indacaterol, glycopyrronium or mometasone furoate between Japanese and Caucasian subjects. Insufficient pharmacokinetic data are available for other ethnicities or races. Total systemic exposure (AUC) for glycopyrronium may be up to 1.8-fold higher in asthma patients with low body weight (35 kg) and up to 2.5-fold higher in asthma patients with low body weight (35 kg) and low absolute GFR (45 ml/min).
No animal studies were performed with the combination of indacaterol, glycopyrronium and mometasone furoate. The non-clinical assessments of each monotherapy and of indacaterol/mometasone and indacaterol/glycopyrronium combination products are presented below:
Effects on the cardiovascular system attributable to the beta2-agonistic properties of indacaterol included tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritation of the nasal cavity and larynx was seen in rodents.
Genotoxicity studies did not reveal any mutagenic or clastogenic potential.
Carcinogenicity was assessed in a two-year rat study and a six-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 beta2-adrenergic agonists. No evidence of carcinogenicity was seen in mice.
All these findings occurred at exposures sufficiently in excess of those anticipated in humans.
Following subcutaneous administration in a rabbit study, adverse effects of indacaterol with respect to pregnancy and embryonal/foetal development could only be demonstrated at doses more than 500-fold those achieved following daily inhalation of 150 mcg in humans (based on AUC0-24 h).
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 peri- and post-natal developmental rat study at an exposure 14-fold higher than in humans treated with indacaterol. Indacaterol was not embryotoxic or teratogenic in rats or rabbits.
Effects attributable to the muscarinic receptor antagonist properties of glycopyrronium included mild to moderate increases in heart rate in dogs, lens opacities in rats and reversible changes associated with reduced glandular secretions in rats and dogs. Mild irritancy or adaptive changes in the respiratory tract were seen in rats. All these findings occurred at exposures sufficiently in excess of those anticipated in humans.
Genotoxicity studies did not reveal any mutagenic or clastogenic potential for glycopyrronium. Carcinogenicity studies in transgenic mice using oral administration and in rats using inhalation administration revealed no evidence of carcinogenicity. Glycopyrronium was not teratogenic in rats or rabbits following inhalation administration.
Glycopyrronium and its metabolites did not significantly cross the placental barrier of pregnant mice, rabbits and dogs. Published data for glycopyrronium in animals do not indicate any reproductive toxicity issues. Fertility and pre- and post-natal development were not affected in rats.
All observed effects are typical of the glucocorticoid class of compounds and are related to exaggerated pharmacological effects of glucocorticoids.
Mometasone furoate showed no genotoxic activity in a standard battery of in vitro and in vivo tests.
In carcinogenicity studies in mice and rats, inhaled mometasone furoate demonstrated no statistically significant increase in the incidence of tumours.
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Effects noted were umbilical hernia in rats, cleft palate in mice and gallbladder agenesis, umbilical hernia and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on foetal growth (lower foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice. In studies of reproductive function, subcutaneous mometasone furoate at 15 mcg/kg prolonged gestation and difficult labour occurred, with a reduction in offspring survival and body weight.
Findings during the nonclinical safety studies of indacaterol/glycopyrronium were consistent with the known pharmacological effects of the indacaterol or glycopyrronium monotherapy components.
The effect on heart rate for indacaterol/glycopyrronium was increased in magnitude and duration compared with the changes observed for each monotherapy component alone.
Shortening of electrocardiograph intervals and decreased systolic and diastolic blood pressure were also apparent. Indacaterol administered to dogs alone or in the indacaterol/glycopyrronium combination was associated with a similar incidence of myocardial lesions.
The findings during the 13-week inhalation toxicity studies were predominantly attributable to the mometasone furoate and were typical pharmacological effects of glucocorticoids. Increased heart rates associated with indacaterol were apparent in dogs after administration of indacaterol/mometasone furoate or indacaterol alone.
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