ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in labeling:Serious Asthma-Related Events Hospitalizations, Intubations, Death see Warnings and Precautions 5.1 ] Oropharyngeal Candidiasis see Warnings and Precautions 5.4 ] Immunosuppression and Risk of Infections see Warnings and Precautions 5.5 )] Hypercorticism and Adrenal Suppression see Warnings and Precautions 5.7 ] Paradoxical Bronchospasm see Warnings and Precautions 5.9 )] Cardiovascular Effects see Warnings and Precautions 5.11 )] Reduction in Bone Mineral Density see Warnings and Precautions 5.12 )] Worsening of Narrow-Angle Glaucoma see Warnings and Precautions 5.13 )] Worsening of Urinary Retention see Warnings and Precautions 5.14 ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Serious Asthma-Related Events Hospitalizations, Intubations, Death see Warnings and Precautions 5.1 ] Oropharyngeal Candidiasis see Warnings and Precautions 5.4 ] Immunosuppression and Risk of Infections see Warnings and Precautions 5.5 )] Hypercorticism and Adrenal Suppression see Warnings and Precautions 5.7 ] Paradoxical Bronchospasm see Warnings and Precautions 5.9 )] Cardiovascular Effects see Warnings and Precautions 5.11 )] Reduction in Bone Mineral Density see Warnings and Precautions 5.12 )] Worsening of Narrow-Angle Glaucoma see Warnings and Precautions 5.13 )] Worsening of Urinary Retention see Warnings and Precautions 5.14 ] Most common adverse reactions (incidence >= 1%) are nasopharyngitis, headache, bronchitis, hypertension, respiratory tract infection viral, pharyngitis, blood pressure increased, viral upper respiratory tract infection, dysphonia, upper respiratory tract infection, influenza, oropharyngeal pain, back pain, rhinitis, anemia, sinusitis, laryngitis, muscle spasms and pneumonia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. The safety of TRIMBOW in asthma is based on the safety data from two randomized, double-blind, parallel-group, active-controlled trials of 52 weeks duration (Trials and 2) that included 2,581 treated adult subjects inadequately controlled on their current treatment of combination therapy (ICS plus LABA) see Clinical Studies 14.1 ]. In the overall population, 61% were female and 99.8% were White; mean age was 53 years. The incidence of adverse reactions occurring in >=1% of the subjects treated with TRIMBOW 100/6/12.5 mcg or TRIMBOW 200/6/12.5 mcg is shown in Table 2. Adverse reactions observed for the groups treated with TRIMBOW were similar to those observed for the beclomethasone dipropionate/formoterol fumarate arms.Table 2. Adverse Reactions with TRIMBOW with >=1% Incidence in Subjects with AsthmaTrial 1Trial 2Adverse Reactionn (%)TRIMBOW100/6/12.5mcg(N=576)BDP/FF100/6mcg(N=574)TRIMBOW200/6/12.5mcg(N=571)BDP/FF200/6mcg(N=573)Nasopharyngitis71 (12)79 (14)46 (8)63 (11)Headache38 (7)46 (8)25 (4)27 (5)Bronchitis18 (3)22 (4)18 (3)18 (3)Hypertension16 (3)9 (2)10 (2)7 (1)Respiratory tract infection viral15 (3)26 (5)17 (3)28 (5)Pharyngitis12 (2)16 (3)10 (2)12 (2)Blood pressure increased12 (2)7 (1)7 (1)8 (1)Viral upper respiratory tract infection12 (2)16 (3)4 (<1)8 (1)Dysphonia11 (2)3 (<1)11 (2)9 (2)Upper respiratory tract infection11 (2)10 (2)9 (2)15 (3)Influenza9 (2)7 (1)7 (1)6 (1)Oropharyngeal pain9 (2)12 (2)6 (1)3 (<1)Back pain8 (1)14 (2)12 (2)5 (<1)Rhinitis8 (1)12 (2)7 (1)12 (2)Anemia8 (1)5 (<1)4 (<1)3 (<1)Sinusitis6 (1)12 (2)6 (1)3 (<1)Laryngitis5 (<1)4 (<1)6 (1)3 (<1)Muscle spasms3 (<1)1 (<1)6 (1)6 (1)Pneumonia2 (<1)4 (<1)7 (1)9 (2). 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of TRIMBOW outside of the United States. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to TRIMBOW or combination of these factors.Cardiac DisordersAtrial fibrillation, tachycardia, palpitations.Eye DisordersVision blurredGastrointestinal disordersDiarrhea, dry mouth, nausea, dyspepsia, stomatitis.General disorders and administration site conditionsAsthenia, fatigue.Immune System DisordersHypersensitivity reactions including erythemaInfections and infestationsUrinary tract infection, oral fungal infection.Metabolism and Nutrition DisordersDecreased appetite Musculoskeletal and Connective Tissue DisordersMyalgia, pain in extremity.Nervous System DisordersTremor, dizziness.Psychiatric DisordersRestlessness, sleep disorder, insomnia.Respiratory, thoracic and mediastinal disordersCough, productive cough, throat irritation, epistaxis, dry throat, dyspnea, pharyngeal inflammation.Skin and subcutaneous tissue disordersDermatitis allergic, rash, pruritus.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Inhalation aerosol: pressurized metered dose inhaler that delivers combination of100 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate per inhalation. 200 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate per inhalation.. 100 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate per inhalation. 200 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate per inhalation.. Inhalation aerosol:100 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate per actuation. (3) 200 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate per actuation. (3) 100 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate per actuation. (3) 200 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate per actuation. (3).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies of carcinogenicity or mutagenicity were conducted with TRIMBOW; however, separate studies of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate are described below. Beclomethasone dipropionateIn 95-week study in rats, beclomethasone dipropionate produced no treatment related increases in the incidence of tumors following oral and inhalation doses (13 weeks at inhalation doses up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg/day), which were approximately 30 times the MRHDID in adults on mg/m2 basis.Beclomethasone dipropionate was not mutagenic or clastogenic in the following tests: Ames assay in bacterial and mammalian cells, chromosomal aberrations in mammalian cells, and micronucleus tests in mice and rats. Formoterol fumarateIn 2-year study in mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at oral doses of 69,000 mcg/kg/day and above, but not at doses up to 50,000 mcg/kg (10,000 times the MRHDID in adults on mg/m2 basis). The incidence of hepatocarcinoma was not increased at oral doses up to 5,000 mcg/kg (1000 times the MRHDID in adults on mg/m2 basis). The incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2,000 mcg/kg/day (400 times the MRHDID in adults on mg/m2 basis) and above. In 2-year study in both rats and mice, the incidence of ovarian leiomyomas was not increased at oral doses up to 5,000 mcg/kg/day (2000 times the MRHDID in adults on mg/m2 basis). The incidence of benign ovarian theca cell tumors was increased at oral doses of 500 mcg/kg/day and above in rats. Glycopyrrolate There was no evidence of treatment-related increases in the incidence of tumors in 2-year inhalation study in rats and an oral 26-week carcinogenicity study in transgenic Tg-rasH2 mice up to the highest dose (447 mcg/kg/day), which is approximately 90 times the MRHDID in adults on mg/m2 basis.Glycopyrrolate was not mutagenic or clastogenic in the following tests: Ames assay in bacterial and mammalian cells, chromosomal aberrations in mammalian cells, and micronucleus tests in mice and rats.Impairment of FertilityThe effects of TRIMBOW on fertility and early embryonic development to implantation were investigated in rats after oral administration. Treatment-related effects noted in females at 20,000 mcg/kg/day were slight increase mean precoital time, reduction of conception rate and fertility index. The number of corpora lutea was significantly reduced and pre-implantation loss was significantly increased. No effect on fertility was detected in female rats at doses up to 2,000 mcg/kg/day (approximately times the MRHDID for the combination of beclomethasone dipropionate/formoterol fumarate/glycopyrrolate), and no effect on male fertility was seen.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action TRIMBOW contains beclomethasone dipropionate, formoterol fumarate and glycopyrrolate. The mechanism of action described below for the individual components applies to TRIMBOW. These drugs represent three different classes of medications (an inhaled corticosteroid, long-acting beta2-adrenergic agonist and an anticholinergic) that have different effects on clinical physiology.Beclomethasone DipropionateBeclomethasone dipropionate is corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism through which beclomethasone dipropionate effects asthma symptoms is not known. Corticosteroids have been shown to have multiple anti-inflammatory effects, inhibiting both inflammatory cells (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines). These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Beclomethasone dipropionate is prodrug that is rapidly activated by hydrolysis to the active monoester, 17-monopropionate (17-BMP). Beclomethasone 17-monopropionate has been shown in vitro to exhibit binding affinity for the human glucocorticoid receptor, which is approximately 13 times that of dexamethasone, times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical relevance of these findings is unknown. Studies in patients with asthma have shown favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of TRIMBOW.Formoterol Fumarate Formoterol fumarate is long-acting selective beta2-adrenergic agonist (beta2-agonist) with rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as bronchodilator. In vitro studies have shown that formoterol fumarate has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects. The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol fumarate, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3,5-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.Glycopyrrolate Glycopyrrolate is long-acting antimuscarinic agent which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. In preclinical in vitro as well as in vivo studies, prevention of acetylcholine, ovalbumin, acetaldehyde and histamine-induced bronchoconstrictive effects was dose-dependent. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly site-specific effect. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyA randomized, double-blind, placebo controlled, single dose study in 95 healthy volunteers assessed the effect of BDP/FF/G on the heart rate corrected QT interval based on the Fridericias correction (QTcF) using electrocardiographic monitoring. The maximum mean (90% two-sided upper confidence bound) difference in QTcF from placebo after baseline correction was 4.4 (5.9) milliseconds and 11.8 (13.4) milliseconds for BDP/FF/G at therapeutic doses and supratherapeutic doses (four times the recommended dosage), respectively, thus excluding the clinically relevant threshold of 10 ms at the therapeutic dose.A dose-dependent increase in heart rate was also observed. The maximum mean (90% two-sided CI) difference in heart rate between BDP/FF/G and placebo after baseline-correction was 3.8 (2.3; 5.4) beats/min observed 10 min post-dose at therapeutic dose and 10.3 (9.3; 11.3) beats/min observed h post-dose at supratherapeutic dose.At the recommended dose, no clinically meaningful effects on cardiac rhythm were observed.HPA Axis EffectsIn adult volunteers, beclomethasone dipropionate at dose of 1000 mcg/day for one month as an oral aerosol demonstrated no suppression of early morning plasma cortisol. However, partial suppression of plasma cortisol was observed when beclomethasone dipropionate was administered in doses of 2000 mcg/day by oral aerosol. Suppression of HPA function (reduction of early morning plasma cortisol levels) has been reported in adult patients who received 1600 mcg daily doses of oral beclomethasone dipropionate for one month. 12.3 Pharmacokinetics. Dose proportional pharmacokinetics (PK) were demonstrated for beclomethasone dipropionate (200 to 800 mcg total daily dose [TDD]), formoterol fumarate (12 to 48 mcg TDD) and glycopyrrolate (25 to 100 mcg TDD), during single dose study in 95 healthy volunteers administering BDP/FF/G at therapeutic and supratherapeutic doses. The systemic exposure to beclomethasone dipropionate, formoterol fumarate and glycopyrrolate has been investigated in pharmacokinetic study conducted in 65 healthy subjects. The study compared the PK of each active component following the administration of single dose of TRIMBOW (4 inhalations of 100/6/12.5 mcg) vs BDP/FF (4 inhalations of 100/6 mcg) and glycopyrrolate (4 inhalations of 12.5 mcg). The pharmacokinetics of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate from TRIMBOW are comparable to the pharmacokinetics of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate when administered as BDP/FF or glycopyrrolate.The dose proportionality of systemic exposure to beclomethasone dipropionate has been investigated in pharmacokinetic study conducted in healthy subjects treated with single dose (4 inhalations) of TRIMBOW 200/6/12.5 mcg or single dose (4 inhalations) of TRIMBOW 100/6/12.5 mcg. TRIMBOW 200/6/12.5 mcg treatment resulted in two times higher systemic exposure to beclomethasone dipropionate and to its main active metabolite (beclomethasone 17-monopropionate) in comparison with TRIMBOW 100/6/12.5 mcg, which is consistent with the different strengths of the two formulations. The systemic exposure to formoterol and glycopyrrolate was similar after the two treatments, although slightly higher peak exposure (Cmax) was observed for glycopyrrolate after administration of TRIMBOW 200/6/12.5 mcg compared with TRIMBOW 100/6/12.5 mcg, notably associated with high inter-subject variability for this parameter.AbsorptionBeclomethasone dipropionateFollowing inhaled administration of TRIMBOW 100/6/12.5 mcg in healthy subjects the median time to reach Cmax was minutes for beclomethasone dipropionate and 30 minutes for beclomethasone 17-monopropionate. The absolute bioavailability following inhalation of beclomethasone dipropionate is approximately 2% and 62% of the nominal dose for unchanged beclomethasone dipropionate and beclomethasone 17-monopropionate, respectively.Formoterol fumarateFollowing inhaled administration of TRIMBOW 100/6/12.5 mcg in healthy subjects the median time to reach Cmax was minutes. Following inhalation, formoterol is absorbed from both the lung and the gastrointestinal tract. At least 65% of the fraction that is swallowed is absorbed from the gastrointestinal tract. Glycopyrrolate Following inhaled administration of TRIMBOW 100/6/12.5 mcg in healthy subjects the median time to reach Cmax was minutes. Following glycopyrrolate inhalation, the lung bioavailability was 10.5% while the absolute bioavailability was 12.8% confirming the limited gastrointestinal absorption. DistributionBeclomethasone dipropionateThe volume of distribution estimated after intravenous administration is 20 for beclomethasone dipropionate and 424 for beclomethasone 17-monopropionate. BDP plasma protein binding is 87%.Formoterol fumarateApparent volume of distribution at steady state in subjects with asthma following inhaled administration of TRIMBOW 100/6/12.5 mcg was estimated to be approximately 1560 L, via population PK analysis. Plasma protein binding of formoterol fumarate is 61-64% with 34% bound to albumin. There was no saturation of binding in the concentration range attained with therapeutic doses. Glycopyrrolate The apparent volume of distribution (Vz) of inhaled glycopyrrolate in healthy subjects was increased compared to intravenous infusion (6,420 versus 323 L), reflecting the slower elimination after inhalation. Glycopyrrolate binding to plasma proteins was 70.98 +- 3.84% and, in the range 50-250 pg/mL, was not concentration dependent.EliminationBeclomethasone dipropionateBeclomethasone dipropionate is excreted in feces in the form of metabolites. Only negligible amounts of unchanged beclomethasone dipropionate and its metabolites have been detected in urine. The mean elimination half-life of beclomethasone dipropionate and beclomethasone 17-monopropionate in subjects with asthma following inhaled administration of TRIMBOW 200/6/12.5 mcg was 0.3 hours and hours, respectively. Formoterol fumarate The excretion of formoterol in urine was studied in seventeen healthy subjects, as part of the investigation of the effect of renal impairment on the pharmacokinetics of inhaled TRIMBOW. In that study, 4.7% of the administered formoterol dose was excreted in urine as free formoterol, while 13.5% of the dose was excreted in urine as total formoterol. The mean elimination half-life of formoterol in subjects with asthma following inhaled administration of TRIMBOW 200/6/12.5 mcg was 6.7 hours.Glycopyrrolate The excretion of glycopyrrolate in urine was studied in seventeen healthy subjects, as part of the investigation of the effect of renal impairment on the pharmacokinetics of inhaled TRIMBOW. In that study, 7% of the administered glycopyrrolate dose was excreted in urine. The mean elimination half-life of glycopyrrolate in subjects with asthma following inhaled administration of TRIMBOW 200/6/12.5 mcg was 21.7 hours.MetabolismBeclomethasone dipropionateBeclomethasone dipropionate is cleared very rapidly from the systemic circulation by metabolism mediated via esterase enzymes found in most tissues, with limited involvement of CYP450. The main product of metabolism of beclomethasone dipropionate is the active metabolite beclomethasone 17-monopropionate. Minor inactive metabolites, beclomethasone 21-monopropionate and beclomethasone, are also formed. Formoterol fumarateFormoterol is widely metabolized, and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2- hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. The liver appears to be the primary site of metabolism. GlycopyrrolateThe metabolic pattern of glycopyrrolate in vitro (humans, dogs, rats, mice and rabbits liver microsomes and hepatocytes) was similar among species and the main metabolic reaction was the hydroxylation on the phenyl or cyclopentyl rings. CYP2D6 was found to be the only enzyme responsible for glycopyrrolate metabolism. Specific PopulationsPopulation pharmacokinetic analysis showed no evidence of clinically significant effect of age, sex, or body weight on the pharmacokinetics of beclomethasone 17-monopropionate, formoterol fumarate or glycopyrrolate.Patients with Hepatic Impairment Dedicated studies of TRIMBOW evaluating effect of hepatic impairment on the pharmacokinetics of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate were not conducted.As formoterol fumarate is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.Patients with Renal Impairment The effect of renal impairment on the exposure to beclomethasone dipropionate, formoterol and glycopyrrolate was evaluated after single administration of inhaled TRIMBOW in subjects with mild, moderate and severe renal impairment (9, and subjects, respectively) in comparison with demographically matching healthy volunteers. Systemic exposure (AUC0-t) to beclomethasone dipropionate, to its metabolite beclomethasone 17-monopropionate and to formoterol fumarate was not affected by mild to severe renal impairment. For glycopyrrolate, there was no impact in subjects with mild and moderate renal impairment. However, an increase in total systemic exposure of up to 2.5-fold was observed in subjects with severe renal impairment (glomerular filtration rate 30 mL/min/1.73 m2), as consequence of significant reduction of the amount excreted in urine (approximately 90% reduction of glycopyrrolate renal clearance). Drug Interaction StudiesNo pharmacokinetic interaction has been observed between beclomethasone dipropionate, formoterol fumarate and glycopyrrolate, when administered in combination by the inhaled route. Specific drug interaction studies of TRIMBOW with other co-administered drugs have not been performed.Cimetidine: At recommended doses, cimetidine, non-specific inhibitor of CYP enzymes and an inhibitor of organic cation transport, had no clinically significant interactions with TRIMBOW.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Figure 1. Adjusted Mean Change from Baseline in Pre-Dose FEV1 (mL) with TRIMBOW 100/6/12.5 mcg over 52 Weeks of Treatment (Trial 1) Figure 2. Adjusted Mean Change from Baseline in Pre-Dose FEV1 (mL) with TRIMBOW 200/6/12.5 mcg over 52 Weeks of Treatment (Trial 2). Figure 3: Adjusted Mean Change from Baseline in ACQ-7 Score over 52 Weeks of Treatment (Pooled Analysis) (ITT Population). 14.1 Asthma. The safety and efficacy of TRIMBOW were evaluated in 2,581 treated subjects in two randomized, double-blind, parallel-group, active-controlled confirmatory trials of 52 weeks duration in adult subjects with asthma inadequately controlled on their current treatments of combination therapy (ICS plus LABA).In Trial (NCT02676076), subjects were randomized to two twice-daily inhalations of TRIMBOW (beclomethasone dipropionate/formoterol fumarate/glycopyrrolate) 100/6/12.5 mcg (N=579) or two twice-daily inhalations of fixed combination of beclomethasone dipropionate and formoterol fumarate 100/6 mcg (N=576). In Trial (NCT02676089) subjects were randomized to two twice-daily inhalations of TRIMBOW (beclomethasone dipropionate/formoterol fumarate/glycopyrrolate) 200/6/12.5 mcg (N=573) or two twice-daily inhalations of fixed combination of beclomethasone dipropionate and formoterol fumarate 200/6 mcg alone (N=576) or in addition to two once-daily inhalations of tiotropium 2.5 mcg (N=288).Subjects with at least one asthma exacerbation requiring systemic corticosteroids or an emergency department visit or hospitalization and an Asthma Control Questionnaire (ACQ-7) score >=1.5 on their current asthma treatment of ICS (greater than beclomethasone dipropionate 500-1000 mcg/day or equivalent) plus LABA entered 2-week run-in period of treatment with beclomethasone dipropionate/formoterol fumarate 100/6 mcg (Trial 1) or beclomethasone dipropionate/formoterol fumarate 200/6 mcg (Trial 2). Subjects who remained inadequately controlled (ACQ-7 score >=1.5) after the run-in period were randomized to receive two twice-daily inhalations of TRIMBOW 100/6/12.5 mcg or two twice-daily inhalations of beclomethasone dipropionate/formoterol fumarate 100/6 mcg [Trial 1] or two twice-daily inhalations of TRIMBOW 200/6/12.5 mcg or two twice-daily inhalations of beclomethasone dipropionate/formoterol fumarate 100/6 mcg or two twice-daily inhalations of beclomethasone dipropionate/formoterol fumarate 200/6 mcg plus two once-daily inhalations of tiotropium 2.5 mcg [Trial 2]. Across all treatment groups, baseline demographics were similar. The majority of subjects were female (61%), White (99.8%), and had never smoked (86%), with mean age of 53 years and mean asthma duration of 25 years (range: to 67). The trial excluded current smokers; past smokers had an average smoking history of 4.7 pack-years. All subjects had at least one documented asthma exacerbation (requiring treatment with systemic corticosteroids or emergency department visit or in-patient hospitalization) in the 12 months prior to screening and 20% reported more than one exacerbation.At screening, the mean pre-bronchodilator percent predicted FEV1 was 53.5% (SD: 13.0%); the mean percent reversibility was 32.9% (SD: 22.6%), with mean absolute reversibility of 498 mL (SD: 288 mL), and the mean ACQ-7 score was 2.69 (SD: 0.61). During the 2-week run-in period, subjects had improvements in both lung function (pre-dose FEV1 improvement of 146 mL) and asthma control (mean ACQ-7 score decreased by 0.32). At randomization, the mean ACQ-7 score was 2.36 and the mean pre-dose percent predicted FEV1 was 58.3% (SD: 12.5%). Lung Function: The co-primary efficacy endpoint was mean change from baseline in pre-dose FEV1 at Week 26. Both TRIMBOW 100/6/12.5 mcg and TRIMBOW 200/6/12.5 mcg showed improvements in lung function compared with beclomethasone dipropionate/formoterol fumarate 100/6 mcg and beclomethasone dipropionate/formoterol fumarate 200/6 mcg, respectively (Table 3, Figures and 2).Table 3. Mean Change from Baseline in Pre-Dose FEV1 (mL) at Week 26Trial 1Trial TRIMBOW 100/6/12.5mcg (N=575) BDP/FF 100/6mcg (N=574) TRIMBOW 200/6/12.5mcg (N=571) BDP/FF 200/6mcg (N=571) 571 567 568 562 Change at Week 26, mean (95% CI) value 185 (155, 214) <0.001 127 (98, 157) <0.001 229 (196, 263) <0.001 157 (123, 190) <0.001 TRIMBOW 100/6/12.5mcg vs. BDP/FF 100/6mcg Difference 95% CI value 57 (15, 99) 0.008 Reference TRIMBOW 200/6/12.5mcg vs. BDP/FF 200/6mcg Difference 95% CI value 73 (26, 120) 0.003 Reference BDP=beclomethasone dipropionate, CI=confidence interval, FF=formoterol fumarate N=Intention-To-Treat (ITT) population and n=number of patients included in the analysis modelFigure 1. Adjusted Mean Change from Baseline in Pre-Dose FEV1 (mL) with TRIMBOW 100/6/12.5 mcg over 52 Weeks of Treatment (Trial 1) Figure 2. Adjusted Mean Change from Baseline in Pre-Dose FEV1 (mL) with TRIMBOW 200/6/12.5 mcg over 52 Weeks of Treatment (Trial 2) The difference in change from baseline in pre-dose FEV1 at Week 26 for TRIMBOW 100/6/12.5 mcg compared with beclomethasone dipropionate/formoterol fumarate 100/6 mcg was 57 mL (95% CI: 15, 99) and for TRIMBOW 200/6/12.5 mcg compared with beclomethasone dipropionate/formoterol fumarate 200/6 mcg was 73 mL (95% CI: 26, 120).Exacerbations: The co-primary endpoint was the rate of moderate and severe exacerbations over the 52-week treatment period. moderate asthma exacerbation was defined as worsening of the signs and symptoms of asthma that did not require the use of systemic corticosteroids for at least days1. severe asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids for at least days. Both TRIMBOW 100/6/12.5 mcg and TRIMBOW 200/6/12.5 mcg showed reduction in moderate and severe exacerbations compared with beclomethasone dipropionate/formoterol fumarate 100/6 mcg and beclomethasone dipropionate/formoterol fumarate 200/6 mcg, respectively (Table 4). Table 4. Moderate1 and Severe2 Asthma Exacerbations Trial Trial Pooled Analysis TRIMBOW100/6/12.5mcg(N=575)BDP/FF100/6mcg(N=574)TRIMBOW200/6/12.5mcg(N=571)BDP/FF200/6mcg(N=571)TRIMBOW(N=1146)BDP/FF(N=1145)Moderate and Severe Asthma ExacerbationsAdjusted exacerbation rate per subject per year(95% CI) 1.825(1.634, 2.037)2.157(1.937, 2.402)1.726(1.543, 1.932)1.963(1.757, 2.192)1.767(1.633, 1.913)2.050(1.897, 2.215)TRIMBOW 100/6/12.5mcg vs. BDP/FF 100/6mcg Adjusted rate ratio 95% CI value 0.846(0.725, 0.987) 0.033 Reference TRIMBOW 200/6/12.5mcg vs. BDP/FF 200/6mcg Adjusted rate ratio 95% CI value 0.880 (0.751, 1.030) 0.110 Reference TRIMBOW vs. BDP/FF Adjusted rate ratio 95% CI value 0.862(0.772, 0.963)0.008ReferenceSevere Asthma ExacerbationsAdjusted exacerbation rate per subject per year(95% CI) 0.204 (0.163,0.255) 0.277 (0.226, 0.339) 0.268 (0.221, 0.324) 0.336 (0.281, 0.402) 0.237(0.205, 0.274)0.309(0.270, 0.353)TRIMBOW 100/6/12.5mcg vs. BDP/FF 100/6mcg Adjusted rate ratio 95% CI value 0.737 (0.551, 0.987) 0.040 Reference TRIMBOW 200/6/12.5mcg vs. BDP/FF 200/6mcg Adjusted rate ratio 95% CI value 0.795 (0.615, 1.027) 0.080 Reference TRIMBOW vs. BDP/FF Adjusted rate ratio 95% CI value 0.767(0.633, 0.930)0.007ReferenceBDP=beclomethasone dipropionate, CI=confidence interval, FF=formoterol fumarateN=ITT population 1Moderate asthma exacerbation was defined as >=1 of criteria listed below and leading to change in treatment: a. Nocturnal awakening(s) due to asthma requiring short-acting beta-agonist for consecutive nights or increase of >=0.75 from baseline in daily symptom score on consecutive days b. Increase from baseline in occasions of short-acting beta-agonist use on consecutive days (minimum increase: puffs/day) c. >=20% decrease in PEF same from baseline on at least consecutive mornings/evenings or >=20% decrease in FEV1 from baseline d. Visit to the emergency department/trial site for asthma treatment not requiring systemic corticosteroids 2Severe asthma exacerbation was defined as an asthma worsening requiring the initiation of treatment with systemic corticosteroids for at least days. Of note, courses of corticosteroids separated by week or more were treated in the analysis as separate severe exacerbations.Health-Related Quality of Life: Additional efficacy measures included Asthma Control Questionnaire (ACQ). The ACQ-7 incorporates questions on symptoms, FEV1, and rescue bronchodilator use and was assessed at weeks 4, 12, 26, 40 and 52. The adjusted mean change from baseline in ACQ-7 total score for the pooled analysis of Trial and Trial is shown in Figure 3. Figure 3: Adjusted Mean Change from Baseline in ACQ-7 Score over 52 Weeks of Treatment (Pooled Analysis) (ITT Population)In descriptive pooled analysis of Trial and Trial 2, the ACQ-7 responder rate, defined as decrease in score of >= 0.5 from baseline, was assessed for TRIMBOW compared with beclomethasone dipropionate/formoterol fumarate at Weeks 26 and 52. At Week 26 and 52, the responder rates for TRIMBOW were 58% and 62%, compared to 53%, and 59% for beclomethasone dipropionate/formoterol fumarate, with Odds Ratios favoring TRIMBOW at Week 26 of 1.22 (95% CI: 1.03, 1.44), and at Week 52 of 1.12 (95% CI: 0.94, 1.32).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. The safety of TRIMBOW in asthma is based on the safety data from two randomized, double-blind, parallel-group, active-controlled trials of 52 weeks duration (Trials and 2) that included 2,581 treated adult subjects inadequately controlled on their current treatment of combination therapy (ICS plus LABA) see Clinical Studies 14.1 ]. In the overall population, 61% were female and 99.8% were White; mean age was 53 years. The incidence of adverse reactions occurring in >=1% of the subjects treated with TRIMBOW 100/6/12.5 mcg or TRIMBOW 200/6/12.5 mcg is shown in Table 2. Adverse reactions observed for the groups treated with TRIMBOW were similar to those observed for the beclomethasone dipropionate/formoterol fumarate arms.Table 2. Adverse Reactions with TRIMBOW with >=1% Incidence in Subjects with AsthmaTrial 1Trial 2Adverse Reactionn (%)TRIMBOW100/6/12.5mcg(N=576)BDP/FF100/6mcg(N=574)TRIMBOW200/6/12.5mcg(N=571)BDP/FF200/6mcg(N=573)Nasopharyngitis71 (12)79 (14)46 (8)63 (11)Headache38 (7)46 (8)25 (4)27 (5)Bronchitis18 (3)22 (4)18 (3)18 (3)Hypertension16 (3)9 (2)10 (2)7 (1)Respiratory tract infection viral15 (3)26 (5)17 (3)28 (5)Pharyngitis12 (2)16 (3)10 (2)12 (2)Blood pressure increased12 (2)7 (1)7 (1)8 (1)Viral upper respiratory tract infection12 (2)16 (3)4 (<1)8 (1)Dysphonia11 (2)3 (<1)11 (2)9 (2)Upper respiratory tract infection11 (2)10 (2)9 (2)15 (3)Influenza9 (2)7 (1)7 (1)6 (1)Oropharyngeal pain9 (2)12 (2)6 (1)3 (<1)Back pain8 (1)14 (2)12 (2)5 (<1)Rhinitis8 (1)12 (2)7 (1)12 (2)Anemia8 (1)5 (<1)4 (<1)3 (<1)Sinusitis6 (1)12 (2)6 (1)3 (<1)Laryngitis5 (<1)4 (<1)6 (1)3 (<1)Muscle spasms3 (<1)1 (<1)6 (1)6 (1)Pneumonia2 (<1)4 (<1)7 (1)9 (2).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. TRIMBOW is contraindicated in the following conditions:Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required see Wa rnings and Precautions 5.2 ]. Hypersensitivity to beclomethasone dipropionate, formoterol fumarate, glycopyrrolate or to any of the excipients [see Warnings and Precautions 5.10 and Description 11 )] . Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required see Wa rnings and Precautions 5.2 ]. Hypersensitivity to beclomethasone dipropionate, formoterol fumarate, glycopyrrolate or to any of the excipients [see Warnings and Precautions 5.10 and Description 11 )] . Primary treatment of status asthmaticus or asthma requiring intensive measures. (4) Severe hypersensitivity to any of the ingredients. (4). Primary treatment of status asthmaticus or asthma requiring intensive measures. (4) Severe hypersensitivity to any of the ingredients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION TRIMBOW (beclomethasone dipropionate, formoterol fumarate and glycopyrrolate) Inhalation Aerosol is pressurized metered-dose inhaler that delivers combination of micronized beclomethasone dipropionate [an inhaled corticosteroid (ICS)], micronized formoterol fumarate [an inhaled long-acting beta2-adrenergic agonist (a LABA)] and micronized glycopyrrolate (an anticholinergic) for oral inhalation.Beclomethasone dipropionate, an inhaled corticosteroid [ICS], has the chemical name [2-[(8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-propanoyloxy-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] propanoate and the following chemical structure:Beclomethasone dipropionate has molecular weight of 521.04218 g/mol, and the molecular formula is C28H37ClO7.Formoterol fumarate, long-acting agonist has the chemical name (E)-but-2-enedioic acid; N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide and the following chemical structure:Formoterol fumarate has molecular weight of 840.91 g/mol, and the molecular formula is C42H52N4O12.Glycopyrrolate, has the chemical name (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate;bromide (R,S)-(S,R) and the following chemical structure:Glycopyrrolate has molecular weight of 398.33452 g/mol, and the molecular formula is C19H28BrNO3. Each nominal metered actuation of TRIMBOW delivers 100 or 200 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate corresponding to targeted delivered dose of 86 or 172 mcg of beclomethasone dipropionate, mcg formoterol fumarate and 11 mcg glycopyrrolate.TRIMBOW contains beclomethasone dipropionate, formoterol fumarate, and glycopyrrolate (BDP/FF/G) in solution formulation resulting in an aerosol with extrafine particles with an average mass median aerodynamic diameter (MMAD) of around 1.1 micrometers and co-deposition of the three components.. Beclomethasone dipropionate, an inhaled corticosteroid [ICS], has the chemical name [2-[(8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-propanoyloxy-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] propanoate and the following chemical structure:. Formoterol fumarate, long-acting agonist has the chemical name (E)-but-2-enedioic acid; N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide and the following chemical structure:. Glycopyrrolate, has the chemical name (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate;bromide (R,S)-(S,R) and the following chemical structure:.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For oral inhalation only. (2.1) inhalations of TRIMBOW 100/6/12.5 mcg micrograms (mcg) twice daily administered by oral inhalation) or inhalations of TRIMBOW 200/6/12.5 mcg twice daily administered by oral inhalation. (2.1). For oral inhalation only. (2.1) 2 inhalations of TRIMBOW 100/6/12.5 mcg micrograms (mcg) twice daily administered by oral inhalation) or inhalations of TRIMBOW 200/6/12.5 mcg twice daily administered by oral inhalation. (2.1). 2.1 Dosage and Administration Overview Administer inhalations twice daily, in the morning and evening. Do not use more than inhalations twice daily, or inhalations in 24 hours. After inhaling, the patient should rinse the mouth with water without swallowing it to help reduce the risk of oropharyngeal candidiasis. No dose adjustment is required in geriatric patients (65 years of age and older), or in patients with mild to moderate renal impairment [see Use in Specific Populations 8.7 )] . Administer inhalations twice daily, in the morning and evening. Do not use more than inhalations twice daily, or inhalations in 24 hours. After inhaling, the patient should rinse the mouth with water without swallowing it to help reduce the risk of oropharyngeal candidiasis. No dose adjustment is required in geriatric patients (65 years of age and older), or in patients with mild to moderate renal impairment [see Use in Specific Populations 8.7 )] . 2.2 Recommen ed Dosage for Maintenance Treatment of Asthma The recommended starting dosage of TRIMBOW is 100 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate (two actuations of TRIMBOW 100/6/12.5 mcg) or 200 mcg beclomethasone dipropionate, mcg formoterol fumarate, and 12.5 mcg glycopyrrolate (two actuations of TRIMBOW 200/6/12.5 mcg), twice daily by oral inhalation. When choosing the starting dose strength of TRIMBOW (100/6/12.5 mcg or 200/6/12.5 mcg), consider the patients disease severity, their previous asthma therapy including the inhaled corticosteroid (ICS) dose as well as the patients current control of asthma symptoms and risk of future exacerbation. The maximum recommended dose is two inhalations of TRIMBOW 200/6/12.5 mcg twice daily. For patients who do not respond adequately to TRIMBOW 100/6/12.5 mcg twice daily, increasing the dose to TRIMBOW 200/6/12.5 mcg twice daily may provide additional improvement in asthma control. For patients who do not respond adequately to TRIMBOW 200/6/12.5 twice daily, re-evaluate and consider other therapeutic regimens and therapeutic options. If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief.. When choosing the starting dose strength of TRIMBOW (100/6/12.5 mcg or 200/6/12.5 mcg), consider the patients disease severity, their previous asthma therapy including the inhaled corticosteroid (ICS) dose as well as the patients current control of asthma symptoms and risk of future exacerbation. The maximum recommended dose is two inhalations of TRIMBOW 200/6/12.5 mcg twice daily. For patients who do not respond adequately to TRIMBOW 100/6/12.5 mcg twice daily, increasing the dose to TRIMBOW 200/6/12.5 mcg twice daily may provide additional improvement in asthma control. For patients who do not respond adequately to TRIMBOW 200/6/12.5 twice daily, re-evaluate and consider other therapeutic regimens and therapeutic options. If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid and cardiovascular effects. (7.1) Other adrenergic drugs may potentiate effect: Use with caution. (7.2) Diuretics, xanthine derivatives or steroids may potentiate hypokalemia or ECG changes. Use with caution. (7.3) Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. (7.4) Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. (7.5) Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium-sparing diuretics may worsen with concomitant beta-agonists. (7.6) Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of TRIMBOW with other anticholinergic-containing drugs. (7.7). Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid and cardiovascular effects. (7.1) Other adrenergic drugs may potentiate effect: Use with caution. (7.2) Diuretics, xanthine derivatives or steroids may potentiate hypokalemia or ECG changes. Use with caution. (7.3) Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. (7.4) Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. (7.5) Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium-sparing diuretics may worsen with concomitant beta-agonists. (7.6) Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of TRIMBOW with other anticholinergic-containing drugs. (7.7). 7.1 Inhibitors of Cytochrome P450 3A4. As beclomethasone dipropionate is mainly metabolized by esterase enzymes, with limited involvement of CYP450, interactions with CYP450 inhibitors are unlikely, but systemic effects with strong CYP3A inhibitors cannot be excluded. Caution should be exercised when considering the coadministration of TRIMBOW with known strong CYP3A4 inhibitors [see Warnings and Precautions 5.8 ), Clinical Pharmacology 12.3 )]. 7.2 Adrenergic Drugs If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol fumarate, component of TRIMBOW, may be potentiated [see Warnings and Precautions 5.3 )]. 7.3 Xanthine Derivatives, Steroids, or Diuretics Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate the hypokalemic effect of beta2-adrenergic agonists such as formoterol fumarate, component of TRIMBOW. 7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and QTc Prolonging Drugs. Formoterol fumarate, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.. 7.5 Beta-adrenergic Receptor Blocking Agents. Beta-blockers not only block the pulmonary effect of beta-agonists, such as formoterol fumarate, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.. 7.6 Non-Potassium-Sparing Diuretics. The electrocardiographic changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium-sparing diuretics.. 7.7 Anticholinergics. There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of TRIMBOW with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions 5.13 5.14 )].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Based on available data, no adjustment of the dosage of TRIMBOW in geriatric patients 65 and above is necessary, but greater sensitivity in some older individuals cannot be ruled out.In Trials and 2, 204 subjects aged 65 years and older, of which subjects were aged 75 years and older, were administered TRIMBOW 100/6/12.5 mcg or TRIMBOW 200/6/12.5 mcg. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between elderly and younger subjects.

HEPATIC IMPAIRMENT SUBSECTION.

8.6 Hepatic Impairment. TRIMBOW has not been studied in subjects with hepatic impairment. Information on the individual components is provided below. Formal pharmacokinetic studies using TRIMBOW have not been conducted in patients with hepatic impairment. However, since formoterol fumarate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of formoterol fumarate in plasma. Therefore, patients with severe hepatic disease should be closely monitored. Beclomethasone dipropionateThe pharmacokinetics of beclomethasone dipropionate in patients with hepatic impairment have not been studied; however, as beclomethasone dipropionate undergoes very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver, to originate the more polar products beclomethasone 21-monopropionate, beclomethasone 17-monopropionate and beclomethasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclomethasone dipropionate.Glycopyrrolate The pharmacokinetics of glycopyrrolate in patients with hepatic impairment have not been studied, however, as glycopyrrolate is predominantly cleared by renal excretion, hepatic impairment is not thought to result in clinically relevant increase of glycopyrrolate systemic exposure.Formoterol fumarateThe pharmacokinetics of formoterol have not been studied in patients with hepatic impairment; however, as formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING TRIMBOW is supplied as pressurized aluminum container, grey plastic actuator with the dose counter on the back, grey mouthpiece and red protective cap for TRIMBOW 100/6/12.5 mcg and green cap for cap for TRIMBOW 200/6/12.5 mcg.Pack SizeStrengthNDC120-inhalation canister(30 day supply)100/6/12.5 mcg NDC 10122-120-02120-inhalation canister(30 day supply)200/6/12.5 mcg NDC 10122-121-02The TRIMBOW container should only be used with the TRIMBOW actuator, and the TRIMBOW actuator should not be used with any other inhalation drug product. Each pressurized container of TRIMBOW is packaged in carton containing one canister and Patient Information leaflet. CounterTRIMBOW has dose counter attached to the canister. The counter starts at 122 and counts down each time spray is released. The correct amount of medication in each actuation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000 or if months have passed since first use date, whichever comes first.Contents under PressureDo not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 122F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children. Do not spray into eyes.Storage:Prior to first use: Store in refrigerator 36-46F (2-8C).After first use: Store the inhaler below 77F (25C) for maximum of two months.Do not freeze. Do not expose to temperatures higher than 122F (50C) as this may cause bursting.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. TRIMBOW is combination of beclomethasone dipropionate (BDP) (an inhaled corticosteroid [ICS]), formoterol fumarate (FF) (a long-acting beta2-adrenergic agonist [LABA]), and glycopyrrolate (G) (an anticholinergic) indicated for the maintenance treatment of asthma in patients aged 18 years and older. (1.1) Limitations of Use Not indicated for relief of acute bronchospasm. (1.2). 1.1 Maintenance Treatment of Asthma TRIMBOW is indicated for the maintenance treatment of asthma in patients aged 18 years and older. 1.2 Limitations of Use TRIMBOW is NOT indicated for relief of acute bronchospasm.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Serious Asthma-Related Events Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with TRIMBOW, there is not significant increase in the risk of these events. [See Warnings and Precautions 5.1 . Not for Acute SymptomsInform patients that TRIMBOW is not meant to relieve acute symptoms of asthma and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them how it should be used. Instruct patients to seek medical attention immediately if they experience any of the following:Decreasing effectiveness of inhaled, short-acting beta2-agonists Need for more inhalations than usual of inhaled, short acting beta2-agonists Significant decrease in lung function as outlined by the physicianTell the patient they should not stop therapy with TRIMBOW without physician/provider guidance since symptoms may recur after discontinuation. [See Warnings and Precautions 5.2 ).] Do Not Use Additional Long-acting Beta2-agonists Instruct patients not to use other LABA for asthma. [See Warnings and Precautions 5.3 ).] Oropharyngeal CandidiasisInform patients that localized infections with Candida albicans occurred in the mouth and pharynx (i.e., thrush) in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with TRIMBOW, but at times therapy with TRIMBOW may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush. [See Warnings and Precautions 5.4 ).] Immunosuppression and Risk of InfectionsWarn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. See Warnings and Precautions 5.5 . Hypercorticism and Adrenal SuppressionAdvise patients that TRIMBOW may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to TRIMBOW. [See Warnings and Precautions 5.7 . Paradoxical BronchospasmAs with other inhaled medicines, TRIMBOW can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue TRIMBOW and contact their healthcare provider right away. [See Warnings and Precautions 5.9 . Hypersensitivity Reactions, including AnaphylaxisAdvise patients that immediate hypersensitivity reactions have been reported after administration. 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, instruct patients to discontinue TRIMBOW immediately. [See Warnings and Precautions 5.10 . Reduction in Bone Mineral DensityAdvise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. See Warnings and Precautions 5.12 . Ocular Effects such as Cataracts or Glaucoma Inform patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations. Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion, and corneal edema). Instruct patients to consult physician immediately if any of these signs or symptoms develop. [See Warnings and Precautions 5.13 . Worsening of Urinary RetentionInstruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult physician immediately if any of these signs or symptoms develop. [See Warnings and Precautions 5.14 . Risks Associated with Beta-agonist TherapyInform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct patients to consult health care practitioner immediately should any of these signs and symptoms develop. [See Warnings and Precautions 5.11 . Manufactured for:Chiesi USA, Inc.Cary, NC 27518USA Manufactured by:Chiesi Farmaceutici, S.p.A.43122 Parma, Italy TRIMBOW is trademark of CHIESI FARMACEUTICI S.P.A..Placeholder Chiesi US text number. Decreasing effectiveness of inhaled, short-acting beta2-agonists Need for more inhalations than usual of inhaled, short acting beta2-agonists Significant decrease in lung function as outlined by the physician. Chiesi.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USETRIMBOW(R)(beclomethasone dipropionate, formoterol fumarate and glycopyrrolate)Inhalation aerosolfor oral inhalation useRead this Instructions for Use before you start using TRIMBOW and each time you get new refill. This information does not take the place of talking to your doctor about your medical condition or treatment. TRIMBOW is available in one size providing 120 actuations.Preparing to use TRIMBOWWrite the date you first use TRIMBOW on the carton box.Check two months have not passed since the first use date. If more than two months have passed, discard your inhaler.Parts of your inhaler (See Figure A)- The metal pressurized container fits into an actuator and holds the medicine.- The plastic mouthpiece delivers the medicine from the pressurized container 1.- The dose counter indicates how many doses are left. Each time you press the pressurized container 1, puff of medicine is released, and the counter will count down by one.- The protective cap covers the mouthpiece when the inhaler is not in use. Before using the inhaler for the first time, you must prime it twice to make sure that it is working properly.Check the dose counter displays 122 doses (See Figure B). Remove the protective cap from the mouthpiece. Hold your inhaler in the upright position with the mouthpiece at the bottom; remove the protective cap. Direct the mouthpiece away from your face and firmly press the pressurized container two times to release two puffs. Check the dose counter. After priming, the dose counter should display 120 remaining doses (See Figure B). Figure AFigure BImportant information you need to know before using TRIMBOWHow to use your inhalerFor oral inhalation use only- Take inhalations of medicine in the morning and inhalations of medicine in the evening. Use the pressurized container only with the actuator supplied with TRIMBOW.- Do not use parts of the TRIMBOW inhaler with parts from any other inhalation medicine.Figure CStep 1.Remove the protective cap from the mouthpiece and check that the mouthpiece is clean and free of any foreign objects (See Figure C).Do not remove the pressurized container from the actuator because:- You may not receive the correct amount of medication.- The dose counter may not function.- Reinsertion may cause the dose counter to count down by one and may discharge puff. Never try to change the numbers on the dose counter or remove the dose counter from the actuator.Figure DStep 2.Breathe out as slowly and fully as you comfortably can through your mouth to empty your lungs (See Figure D). Do not breathe into the inhaler.Figure EStep 3. Hold the inhaler upright with the mouthpiece at the bottom and place the mouthpiece into mouth and close lips around the mouthpiece (See Figure E). Figure FStep 4.Breathe in slowly and deeply through your mouth to fill your lungs with air and at the same time, press down firmly and fully on the top of the pressurized container until it stops moving in the actuator. Take your finger off the pressurized container (See Figure F).Cleaning your TRIMBOW inhaler The mouthpiece should be cleaned after every days of use. It is very important to keep your inhaler clean so that medicine will not build up.Figure GStep 5.When you have finished breathing in, hold your breath as long as you can, up to 10 seconds. Then, remove the inhaler from your mouth and breathe out slowly through your nose, while keeping your lips closed (See Figure G). Do not breathe out through your inhaler. Wait at least 30 seconds, then take another inhalation, following the instructions starting again from step 2.Routine cleaning instructions:.- Do not remove the pressurized container from the inhaler.- Remove the protective cap from the mouthpiece.- Wipe the inside and outside surfaces of the mouthpiece with clean, dry, lint free cloth or tissue.- Do not use water or other liquids to clean your inhaler.- Replace the cap on the mouthpiece after cleaning.- Do not remove the container from the actuator.Step 6.Check the dose counter displays the number of puffs left in your inhaler.Storing TRIMBOWPrior to first use:Store in refrigerator (36F to 46F, 2C to 8C).Step 7.Wait at least 30 seconds to take your second inhalation. Keep the inhaler in the upright position and repeat steps to 6.After first use:Store the inhaler below 77F (25C) for maximum of two monthsFigure HAfter using your inhalerStep 8.After use, replace the protective cap (See Figure H).- Keep your inhaler out of the sight and reach of children- The inhaler can be stored in any position- Do not put hole in or throw the container into fire or incinerator. Do not use or store it near heat or open flame. Exposure to temperatures above 122F (50C) may cause bursting.- Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month.- Do not use this medicine more than two months after the first use date.Step 9.Rinse your mouth with water without swallowing it.Disposing of TRIMBOWThrow the empty inhaler away in your household trash out of reach of children and pets.When to get new inhalerIt is important that you pay attention to the number of puffs left in your inhaler by checking the dose counter.You should get refill when the counter shows the number 20.Stop using the inhaler when the dose counter reaches 0, as any medicine left in the inhaler may not be enough to give you full dose.Manufactured by:Chiesi Farmaceutici S.p.A.43122 Parma Italy Manufactured for:Chiesi USA, Inc. Cary, NC 27518 USA1-888-661-9260 TRIMBOW is registered in the US Patent and Trademark Office.All trademarks referenced herein are the property of their prospective owners.For more information about TRIMBOW, call 1-888-661-9260. This Instructions for Use has been approved by the U.S. Food and Drug Administration XX/20XX CTT- XXX-XXXX-00-W. Check the dose counter displays 122 doses (See Figure B). Remove the protective cap from the mouthpiece. Hold your inhaler in the upright position with the mouthpiece at the bottom; remove the protective cap. Direct the mouthpiece away from your face and firmly press the pressurized container two times to release two puffs. Check the dose counter. After priming, the dose counter should display 120 remaining doses (See Figure B). Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H.

LACTATION SECTION.

8.2 Lactation Risk Summary There is no information available on the presence of beclomethasone dipropionate, formoterol fumarate or glycopyrrolate in human milk; the effects on the breastfed child; or the effects on milk production. Glucocorticoids are excreted in human milk. It is reasonable to assume that beclomethasone dipropionate and its metabolites are also excreted in human milk. It is unknown whether formoterol fumarate or glycopyrrolate (including their metabolites) are excreted in human milk, but they have been detected in the milk of lactating animals. Anticholinergics like glycopyrrolate could suppress lactation. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TRIMBOW and any potential adverse effects on the breast-fed child from TRIMBOW or from the underlying maternal condition. DataAnimal DataThere is no available data on the exposure and effects of TRIMBOW in rat pups. Formoterol FumarateIn the fertility and reproduction study in rats, plasma levels of formoterol were measured in pups on post-natal day 15. It was estimated that the maximum plasma concentration that the pups received from the maternal animal, at the highest dose of 15 mg/kg, after nursing was 4.4% (0.24 nmol/L for litter vs. 5.5 nmol/L for the mother). GlycopyrrolateIn the reproductive/developmental toxicity study in rats, plasma levels of glycopyrrolate were measured in pups on post-natal day 4. The maximum concentration in the pups was 6% of the maternal dose of 10 mg/kg/day (pup plasma concentration of 96 ng/mL at hour after dosing corresponded with 1610 ng/mL in the dam at 0.5 hours after dosing).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action TRIMBOW contains beclomethasone dipropionate, formoterol fumarate and glycopyrrolate. The mechanism of action described below for the individual components applies to TRIMBOW. These drugs represent three different classes of medications (an inhaled corticosteroid, long-acting beta2-adrenergic agonist and an anticholinergic) that have different effects on clinical physiology.Beclomethasone DipropionateBeclomethasone dipropionate is corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism through which beclomethasone dipropionate effects asthma symptoms is not known. Corticosteroids have been shown to have multiple anti-inflammatory effects, inhibiting both inflammatory cells (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines). These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Beclomethasone dipropionate is prodrug that is rapidly activated by hydrolysis to the active monoester, 17-monopropionate (17-BMP). Beclomethasone 17-monopropionate has been shown in vitro to exhibit binding affinity for the human glucocorticoid receptor, which is approximately 13 times that of dexamethasone, times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical relevance of these findings is unknown. Studies in patients with asthma have shown favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of TRIMBOW.Formoterol Fumarate Formoterol fumarate is long-acting selective beta2-adrenergic agonist (beta2-agonist) with rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as bronchodilator. In vitro studies have shown that formoterol fumarate has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects. The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol fumarate, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3,5-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.Glycopyrrolate Glycopyrrolate is long-acting antimuscarinic agent which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. In preclinical in vitro as well as in vivo studies, prevention of acetylcholine, ovalbumin, acetaldehyde and histamine-induced bronchoconstrictive effects was dose-dependent. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly site-specific effect.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies of carcinogenicity or mutagenicity were conducted with TRIMBOW; however, separate studies of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate are described below. Beclomethasone dipropionateIn 95-week study in rats, beclomethasone dipropionate produced no treatment related increases in the incidence of tumors following oral and inhalation doses (13 weeks at inhalation doses up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg/day), which were approximately 30 times the MRHDID in adults on mg/m2 basis.Beclomethasone dipropionate was not mutagenic or clastogenic in the following tests: Ames assay in bacterial and mammalian cells, chromosomal aberrations in mammalian cells, and micronucleus tests in mice and rats. Formoterol fumarateIn 2-year study in mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at oral doses of 69,000 mcg/kg/day and above, but not at doses up to 50,000 mcg/kg (10,000 times the MRHDID in adults on mg/m2 basis). The incidence of hepatocarcinoma was not increased at oral doses up to 5,000 mcg/kg (1000 times the MRHDID in adults on mg/m2 basis). The incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2,000 mcg/kg/day (400 times the MRHDID in adults on mg/m2 basis) and above. In 2-year study in both rats and mice, the incidence of ovarian leiomyomas was not increased at oral doses up to 5,000 mcg/kg/day (2000 times the MRHDID in adults on mg/m2 basis). The incidence of benign ovarian theca cell tumors was increased at oral doses of 500 mcg/kg/day and above in rats. Glycopyrrolate There was no evidence of treatment-related increases in the incidence of tumors in 2-year inhalation study in rats and an oral 26-week carcinogenicity study in transgenic Tg-rasH2 mice up to the highest dose (447 mcg/kg/day), which is approximately 90 times the MRHDID in adults on mg/m2 basis.Glycopyrrolate was not mutagenic or clastogenic in the following tests: Ames assay in bacterial and mammalian cells, chromosomal aberrations in mammalian cells, and micronucleus tests in mice and rats.Impairment of FertilityThe effects of TRIMBOW on fertility and early embryonic development to implantation were investigated in rats after oral administration. Treatment-related effects noted in females at 20,000 mcg/kg/day were slight increase mean precoital time, reduction of conception rate and fertility index. The number of corpora lutea was significantly reduced and pre-implantation loss was significantly increased. No effect on fertility was detected in female rats at doses up to 2,000 mcg/kg/day (approximately times the MRHDID for the combination of beclomethasone dipropionate/formoterol fumarate/glycopyrrolate), and no effect on male fertility was seen.

OVERDOSAGE SECTION.

10 OVERDOSAGE. TRIMBOW contains beclomethasone dipropionate, formoterol fumarate, and glycopyrrolate; therefore, the risks associated with overdosage for the individual components described below apply to TRIMBOW. Treatment of overdosage consists of discontinuation of TRIMBOW together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.Beclomethasone DipropionateIf used at excessive doses for prolonged periods, systemic corticosteroid effects, such as hypercorticism may occur see Warnings and Precautions 5.7 ]. Formoterol Fumarate An overdose of formoterol fumarate would likely lead to an exaggeration of effects that are typical for beta2-agonists: seizures, angina, hypertension, hypotension, tachycardia, atrial and ventricular tachyarrhythmias, nervousness, headache, tremor, palpitations, muscle cramps, nausea, dizziness, sleep disturbances, metabolic acidosis, hyperglycemia, hypokalemia. As with all sympathomimetic medications, cardiac arrest, and even death may be associated with overdosage of formoterol fumarate.Glycopyrrolate High doses of glycopyrrolate, component of TRIMBOW, may lead to anticholinergic signs and symptoms such as nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure (causing pain, vision disturbances or reddening of the eye), obstipation, or difficulties in voiding.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. TRIMBOW(R) (beclomethasone dipropionate/formoterol fumarate/glycopyrrolate) 200 mcg/6 mcg/12.5 mcgper inhalation1 pressurized container of120 inhalationNDC 10122-121-02Rx Only. PRINCIPAL DISPLAY PANELTRIMBOW(R)(beclomethasone dipropionate/formoterol fumarate/glycopyrrolate) 200 mcg/6 mcg/12.5 mcgper inhalation1 pressurized container of120 inhalationNDC 10122-121-02Rx Only.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of TRIMBOW have not been established in pediatric patients (aged 17 years and younger). TRIMBOW is not indicated for use in pediatric patients.Effects on GrowthOrally inhaled corticosteroids may cause reduction in growth velocity when administered to children and adolescents.Controlled clinical trials have shown that ICS may cause reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately cm/year (range: 0.3 to 1.8 cm/year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyA randomized, double-blind, placebo controlled, single dose study in 95 healthy volunteers assessed the effect of BDP/FF/G on the heart rate corrected QT interval based on the Fridericias correction (QTcF) using electrocardiographic monitoring. The maximum mean (90% two-sided upper confidence bound) difference in QTcF from placebo after baseline correction was 4.4 (5.9) milliseconds and 11.8 (13.4) milliseconds for BDP/FF/G at therapeutic doses and supratherapeutic doses (four times the recommended dosage), respectively, thus excluding the clinically relevant threshold of 10 ms at the therapeutic dose.A dose-dependent increase in heart rate was also observed. The maximum mean (90% two-sided CI) difference in heart rate between BDP/FF/G and placebo after baseline-correction was 3.8 (2.3; 5.4) beats/min observed 10 min post-dose at therapeutic dose and 10.3 (9.3; 11.3) beats/min observed h post-dose at supratherapeutic dose.At the recommended dose, no clinically meaningful effects on cardiac rhythm were observed.HPA Axis EffectsIn adult volunteers, beclomethasone dipropionate at dose of 1000 mcg/day for one month as an oral aerosol demonstrated no suppression of early morning plasma cortisol. However, partial suppression of plasma cortisol was observed when beclomethasone dipropionate was administered in doses of 2000 mcg/day by oral aerosol. Suppression of HPA function (reduction of early morning plasma cortisol levels) has been reported in adult patients who received 1600 mcg daily doses of oral beclomethasone dipropionate for one month.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Dose proportional pharmacokinetics (PK) were demonstrated for beclomethasone dipropionate (200 to 800 mcg total daily dose [TDD]), formoterol fumarate (12 to 48 mcg TDD) and glycopyrrolate (25 to 100 mcg TDD), during single dose study in 95 healthy volunteers administering BDP/FF/G at therapeutic and supratherapeutic doses. The systemic exposure to beclomethasone dipropionate, formoterol fumarate and glycopyrrolate has been investigated in pharmacokinetic study conducted in 65 healthy subjects. The study compared the PK of each active component following the administration of single dose of TRIMBOW (4 inhalations of 100/6/12.5 mcg) vs BDP/FF (4 inhalations of 100/6 mcg) and glycopyrrolate (4 inhalations of 12.5 mcg). The pharmacokinetics of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate from TRIMBOW are comparable to the pharmacokinetics of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate when administered as BDP/FF or glycopyrrolate.The dose proportionality of systemic exposure to beclomethasone dipropionate has been investigated in pharmacokinetic study conducted in healthy subjects treated with single dose (4 inhalations) of TRIMBOW 200/6/12.5 mcg or single dose (4 inhalations) of TRIMBOW 100/6/12.5 mcg. TRIMBOW 200/6/12.5 mcg treatment resulted in two times higher systemic exposure to beclomethasone dipropionate and to its main active metabolite (beclomethasone 17-monopropionate) in comparison with TRIMBOW 100/6/12.5 mcg, which is consistent with the different strengths of the two formulations. The systemic exposure to formoterol and glycopyrrolate was similar after the two treatments, although slightly higher peak exposure (Cmax) was observed for glycopyrrolate after administration of TRIMBOW 200/6/12.5 mcg compared with TRIMBOW 100/6/12.5 mcg, notably associated with high inter-subject variability for this parameter.AbsorptionBeclomethasone dipropionateFollowing inhaled administration of TRIMBOW 100/6/12.5 mcg in healthy subjects the median time to reach Cmax was minutes for beclomethasone dipropionate and 30 minutes for beclomethasone 17-monopropionate. The absolute bioavailability following inhalation of beclomethasone dipropionate is approximately 2% and 62% of the nominal dose for unchanged beclomethasone dipropionate and beclomethasone 17-monopropionate, respectively.Formoterol fumarateFollowing inhaled administration of TRIMBOW 100/6/12.5 mcg in healthy subjects the median time to reach Cmax was minutes. Following inhalation, formoterol is absorbed from both the lung and the gastrointestinal tract. At least 65% of the fraction that is swallowed is absorbed from the gastrointestinal tract. Glycopyrrolate Following inhaled administration of TRIMBOW 100/6/12.5 mcg in healthy subjects the median time to reach Cmax was minutes. Following glycopyrrolate inhalation, the lung bioavailability was 10.5% while the absolute bioavailability was 12.8% confirming the limited gastrointestinal absorption. DistributionBeclomethasone dipropionateThe volume of distribution estimated after intravenous administration is 20 for beclomethasone dipropionate and 424 for beclomethasone 17-monopropionate. BDP plasma protein binding is 87%.Formoterol fumarateApparent volume of distribution at steady state in subjects with asthma following inhaled administration of TRIMBOW 100/6/12.5 mcg was estimated to be approximately 1560 L, via population PK analysis. Plasma protein binding of formoterol fumarate is 61-64% with 34% bound to albumin. There was no saturation of binding in the concentration range attained with therapeutic doses. Glycopyrrolate The apparent volume of distribution (Vz) of inhaled glycopyrrolate in healthy subjects was increased compared to intravenous infusion (6,420 versus 323 L), reflecting the slower elimination after inhalation. Glycopyrrolate binding to plasma proteins was 70.98 +- 3.84% and, in the range 50-250 pg/mL, was not concentration dependent.EliminationBeclomethasone dipropionateBeclomethasone dipropionate is excreted in feces in the form of metabolites. Only negligible amounts of unchanged beclomethasone dipropionate and its metabolites have been detected in urine. The mean elimination half-life of beclomethasone dipropionate and beclomethasone 17-monopropionate in subjects with asthma following inhaled administration of TRIMBOW 200/6/12.5 mcg was 0.3 hours and hours, respectively. Formoterol fumarate The excretion of formoterol in urine was studied in seventeen healthy subjects, as part of the investigation of the effect of renal impairment on the pharmacokinetics of inhaled TRIMBOW. In that study, 4.7% of the administered formoterol dose was excreted in urine as free formoterol, while 13.5% of the dose was excreted in urine as total formoterol. The mean elimination half-life of formoterol in subjects with asthma following inhaled administration of TRIMBOW 200/6/12.5 mcg was 6.7 hours.Glycopyrrolate The excretion of glycopyrrolate in urine was studied in seventeen healthy subjects, as part of the investigation of the effect of renal impairment on the pharmacokinetics of inhaled TRIMBOW. In that study, 7% of the administered glycopyrrolate dose was excreted in urine. The mean elimination half-life of glycopyrrolate in subjects with asthma following inhaled administration of TRIMBOW 200/6/12.5 mcg was 21.7 hours.MetabolismBeclomethasone dipropionateBeclomethasone dipropionate is cleared very rapidly from the systemic circulation by metabolism mediated via esterase enzymes found in most tissues, with limited involvement of CYP450. The main product of metabolism of beclomethasone dipropionate is the active metabolite beclomethasone 17-monopropionate. Minor inactive metabolites, beclomethasone 21-monopropionate and beclomethasone, are also formed. Formoterol fumarateFormoterol is widely metabolized, and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2- hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. The liver appears to be the primary site of metabolism. GlycopyrrolateThe metabolic pattern of glycopyrrolate in vitro (humans, dogs, rats, mice and rabbits liver microsomes and hepatocytes) was similar among species and the main metabolic reaction was the hydroxylation on the phenyl or cyclopentyl rings. CYP2D6 was found to be the only enzyme responsible for glycopyrrolate metabolism. Specific PopulationsPopulation pharmacokinetic analysis showed no evidence of clinically significant effect of age, sex, or body weight on the pharmacokinetics of beclomethasone 17-monopropionate, formoterol fumarate or glycopyrrolate.Patients with Hepatic Impairment Dedicated studies of TRIMBOW evaluating effect of hepatic impairment on the pharmacokinetics of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate were not conducted.As formoterol fumarate is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.Patients with Renal Impairment The effect of renal impairment on the exposure to beclomethasone dipropionate, formoterol and glycopyrrolate was evaluated after single administration of inhaled TRIMBOW in subjects with mild, moderate and severe renal impairment (9, and subjects, respectively) in comparison with demographically matching healthy volunteers. Systemic exposure (AUC0-t) to beclomethasone dipropionate, to its metabolite beclomethasone 17-monopropionate and to formoterol fumarate was not affected by mild to severe renal impairment. For glycopyrrolate, there was no impact in subjects with mild and moderate renal impairment. However, an increase in total systemic exposure of up to 2.5-fold was observed in subjects with severe renal impairment (glomerular filtration rate 30 mL/min/1.73 m2), as consequence of significant reduction of the amount excreted in urine (approximately 90% reduction of glycopyrrolate renal clearance). Drug Interaction StudiesNo pharmacokinetic interaction has been observed between beclomethasone dipropionate, formoterol fumarate and glycopyrrolate, when administered in combination by the inhaled route. Specific drug interaction studies of TRIMBOW with other co-administered drugs have not been performed.Cimetidine: At recommended doses, cimetidine, non-specific inhibitor of CYP enzymes and an inhibitor of organic cation transport, had no clinically significant interactions with TRIMBOW.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of TRIMBOW outside of the United States. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to TRIMBOW or combination of these factors.Cardiac DisordersAtrial fibrillation, tachycardia, palpitations.Eye DisordersVision blurredGastrointestinal disordersDiarrhea, dry mouth, nausea, dyspepsia, stomatitis.General disorders and administration site conditionsAsthenia, fatigue.Immune System DisordersHypersensitivity reactions including erythemaInfections and infestationsUrinary tract infection, oral fungal infection.Metabolism and Nutrition DisordersDecreased appetite Musculoskeletal and Connective Tissue DisordersMyalgia, pain in extremity.Nervous System DisordersTremor, dizziness.Psychiatric DisordersRestlessness, sleep disorder, insomnia.Respiratory, thoracic and mediastinal disordersCough, productive cough, throat irritation, epistaxis, dry throat, dyspnea, pharyngeal inflammation.Skin and subcutaneous tissue disordersDermatitis allergic, rash, pruritus.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary There are insufficient data on the use of TRIMBOW or its individual components, beclomethasone dipropionate, formoterol fumarate, and glycopyrrolate, in pregnant women to inform drug-associated risk. See Clinical Considerations.) Studies in animals have shown reproductive toxicity. Beclomethasone dipropionate was considered responsible for reproductive toxicity effects in rats such as reduction of the conception rate, fertility index, early embryonic development parameters (implantation loss), delay in ossification and increased incidence of visceral variations. Tocolytic and antimuscarinic effects, attributed to the beta2-adrenergic activity of formoterol fumarate and the antimuscarinic activity of glycopyrrolate, affected pregnant rats in the late phase of gestation and/or early phase of lactation, leading to loss of pups. The estimated risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored, and medication adjusted as necessary to maintain optimal control of asthma. Labor or Delivery:There are no well-controlled human trials that have investigated the effects of TRIMBOW on preterm labor or labor at term. TRIMBOW should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.Infants and neonates born to mothers receiving substantial doses should be observed for adrenal suppression. If treatment during pregnancy is necessary, the lowest effective dose should be used. Data Animal DataThe effects of TRIMBOW on fertility, early embryonic development to implantation and fetal and post-natal development were investigated in rats after oral administration. The reproduction studies determined safe levels in the rat, but also clearly highlighted the known corticosteroid-related effects on maternal and fetal toxicity. No effects on male fertility were seen, but reduced female fertility, embryonic implantation and fetal development were observed from the dose of mg/kg/day (this dose is 18, 37 and 77 times the maximum clinical dose as body surface for BDP, FF and respectively). Furthermore, the contribution of in the observed effects on food consumption, bodyweight and general tolerability by the dams was also significant. For these reasons, the possible benefits of the drug must be weighed against the possible risks during pregnancy. No additional side effects have been observed with respect to the single agents.

RENAL IMPAIRMENT SUBSECTION.

8.7 Renal Impairment. TRIMBOW can be used at the recommended dose in patients with mild (glomerular filtration rate [GFR] >=50 to <80 mL/min/1.73 m2) to moderate (GFR >=30 to <50 mL/min/1.73 m2) renal impairment. Use in patients with severe (GFR <30 mL/min/1.73 m2) renal impairment or end-stage renal (GFR <15 mL/min/1.73 m2) disease requiring dialysis, especially if associated with significant body weight reduction, should be considered only if the expected benefit outweighs the potential risk.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationTRIMBOW(R) (trim-bow)(beclomethasone dipropionate, formoterol fumarate and glycopyrrolate) inhalation aerosolfor oral inhalation useWhat is TRIMBOWTRIMBOW combines medicines in inhaler, an inhaled corticosteroid (ICS) medicine (beclomethasone dipropionate), long-acting beta2-adrenergic agonist (LABA) medicine (formoterol fumarate) and an anticholinergic medicine (glycopyrrolate). ICS medicines like beclomethasone dipropionate help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems. LABA medicines such as formoterol fumarate and anticholinergic medicines such as glycopyrrolate help the muscles around the airways in your lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe. TRIMBOW is prescription medicine used long term (chronic) to prevent and control symptoms of asthma for better breathing, prevent symptoms such as wheezing and reduce the number of flare-ups (the worsening of your asthma symptoms). TRIMBOW is not used to relieve sudden breathing problems and will not replace rescue inhaler. TRIMBOW contains formoterol fumarate. LABA medicines such as formoterol fumarate when used alone increase the risk of hospitalizations and death from asthma problems. TRIMBOW contains an ICS, LABA and an anticholinergic. When an ICS and LABA are used together, there is not significant increased risk in hospitalizations and death from asthma problems. TRIMBOW should not be used in children younger than 18 years of age.It is not known if TRIMBOW is safe and effective in children younger than 18 years of age. Do not use TRIMBOW: to treat sudden, severe symptoms of asthma. if you are allergic to beclomethasone dipropionate, formoterol fumarate, glycopyrrolate or any of the ingredients in TRIMBOW. See the end of this Patient Information for complete list of ingredients in TRIMBOW. Before using TRIMBOW, tell your healthcare provider about all of your medical conditions, including if you: have heart problems. have high blood pressure. have seizures. have thyroid problems. have diabetes. have liver problems. have weak bones (osteoporosis). have an immune system problem. have eye problems such as glaucoma, increased pressure in your eye, cataracts, blurred vision, or other changes in vision. TRIMBOW may make your glaucoma worse. have prostate or bladder problems, or problems passing urine. TRIMBOW may make these problems worse. have any type of viral, bacterial, parasitic, or fungal infection. are exposed to chickenpox or measles. are pregnant or plan to become pregnant. It is not known if TRIMBOW may harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if the medicines in TRIMBOW pass into your breast milk and if they can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TRIMBOW and certain other medicines may interact with each other. This may cause serious side effects. Especially tell your healthcare provider if you take: anticholinergics (including tiotropium, ipratropium, aclidinium) atropine other LABA (including salmeterol, formoterol fumarate, arformoterol, vilanterol, olodaterol, and indacaterol) antifungal or anti-HIV medicines. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. How should use TRIMBOWRead the step-by-step instructions for using TRIMBOW at the end of this Patient Information. Do not use TRIMBOW unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly. TRIMBOW comes in different strengths. Your healthcare provider prescribed the strength that is best for you. If you have been using different inhaler containing beclomethasone dipropionate previously, ask your doctor for advice, as the effective dose of beclomethasone dipropionate in TRIMBOW for the treatment of your asthma may be lower than that of some other inhalers. Use TRIMBOW exactly as your healthcare provider tells you to use it. Do not use TRIMBOW more often than prescribed. Use inhalations of TRIMBOW, times each day (2 puffs in the morning and puffs in the evening). If you miss dose of TRIMBOW, take it as soon as you remember. Do not take more than inhalations per day. Take your next dose at your usual time. If you take too much TRIMBOW, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness. Do not use other medicines that contain LABA or an anticholinergic for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA or anticholinergic medicines. Do not stop using TRIMBOW unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed. TRIMBOW does not relieve sudden symptoms of asthma and you should not take extra doses of TRIMBOW to relieve these sudden symptoms. Always have rescue inhaler with you to treat sudden symptoms. If you do not have rescue inhaler, call your healthcare provider to have one prescribed for you. Call your healthcare provider or get medical care right away if: your breathing problems get worse. you need to use your rescue inhaler more often than usual. your rescue inhaler does not work as well to relieve your symptoms. What are the possible side effects of TRIMBOW TRIMBOW can cause serious side effects, including: fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using TRIMBOW to help reduce your chance of getting thrush. weakened immune system and increased chance of getting infections (immunosuppression).reduced adrenal function (adrenal insufficiency). Adrenal insufficiency is condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking medicine containing an ICS (such as TRIMBOW). During this transition period, when your body is under stress from fever, trauma (such as car accident), infection, surgery, or worse asthma symptoms, adrenal insufficiency can get worse and may cause death. Symptoms of adrenal insufficiency include: feeling tiredo nausea and vomiting lack of energyo low blood pressure (hypotension) weaknesssudden breathing problems immediately after inhaling your medicine. If you have sudden breathing problems immediately after inhaling your medicine, stop using TRIMBOW and call your healthcare provider right away. serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of serious allergic reaction: rasho swelling of your face, mouth and tongue hiveso breathing problemseffects on heart. Increased blood pressureo Chest pain A fast or irregular heartbeat, awareness of heartbeateffects on nervous system. tremoro nervousnessbone thinning or weakness (osteoporosis).eye problems including glaucoma, increased pressure in your eye, cataracts, blurred vision, worsening of narrow-angle glaucoma, or other changes in vision. You should have regular eye exams while using TRIMBOW. Acute narrow-angle glaucoma can cause permanent loss of vision if not treated. Symptoms of acute narrow-angle glaucoma may include: eye pain or discomforto seeing halos or bright colors around lights nausea or vomitingo red eyes blurred visionIf you have these symptoms, call your healthcare provider right away before taking another dose. urinary retention. People who take TRIMBOW may develop new or worse urinary retention. Symptoms of urinary retention may include: difficulty urinatingo urinating frequently painful urinationo urination in weak stream or dripsIf you have these symptoms of urinary retention, stop taking TRIMBOW, and call your healthcare provider right away before taking another dose. changes in laboratory blood values, including high levels of blood sugar (hyperglycemia) and low levels of potassium (hypokalemia). slowed growth in children. Common side effects of TRIMBOW include:itchy, runny or blocked nose sore throat headache bronchitis high blood pressure respiratory tract infection hoarseness or laryngitis fluback pain inflammation of the nasal lining low red blood cells (anemia) inflammation of the sinuses inflammation of throat muscle spasms pneumonia mouth and throat painThese are not all the possible side effects of TRIMBOW. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Chiesi USA, Inc. at 1-888-661-9260.How should store TRIMBOWPrior to first use: Store in refrigerator 36F to 46F (2C to 8C). After first use: Store at room temperature 68F to 77F (20C to 25C) for maximum of months. Throw away TRIMBOW months after you remove from the refrigerator, or when the dose counter reaches zero 0, whichever comes first. Do not put hole in the TRIMBOW canister. Do not throw the canister into fire or incinerator. Do not use or store it near heat or open flame. Temperatures higher than 122F (50C) may cause bursting.Keep TRIMBOW and all medicines out of the reach of children.General information about the safe and effective use of TRIMBOW.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TRIMBOW for condition for which it was not prescribed. Do not give TRIMBOW to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about TRIMBOW that is written for health professionals. What are the ingredients in TRIMBOW Active ingredients: beclomethasone dipropionate, formoterol fumarate and glycopyrrolate Inactive ingredients: ethanol anhydrous and hydrochloric acid Propellant: norflurane (HFA 134a) Manufactured by:Chiesi Farmaceutici S.p.A.43122 Parma Italy Manufactured for: Chiesi USA, Inc. Cary, NC 27518 USA 1-888-661-9260 TRIMBOW is registered in the US Patent and Trademark Office.All trademarks referenced herein are the property of their prospective owners. For more information about TRIMBOW, call 1-888-661-9260.This Patient Information has been approved by the U.S. Food and Drug Administration XX/2026. TRIMBOW combines medicines in inhaler, an inhaled corticosteroid (ICS) medicine (beclomethasone dipropionate), long-acting beta2-adrenergic agonist (LABA) medicine (formoterol fumarate) and an anticholinergic medicine (glycopyrrolate). ICS medicines like beclomethasone dipropionate help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems. LABA medicines such as formoterol fumarate and anticholinergic medicines such as glycopyrrolate help the muscles around the airways in your lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe. TRIMBOW is prescription medicine used long term (chronic) to prevent and control symptoms of asthma for better breathing, prevent symptoms such as wheezing and reduce the number of flare-ups (the worsening of your asthma symptoms). TRIMBOW is not used to relieve sudden breathing problems and will not replace rescue inhaler. TRIMBOW contains formoterol fumarate. LABA medicines such as formoterol fumarate when used alone increase the risk of hospitalizations and death from asthma problems. TRIMBOW contains an ICS, LABA and an anticholinergic. When an ICS and LABA are used together, there is not significant increased risk in hospitalizations and death from asthma problems. to treat sudden, severe symptoms of asthma. if you are allergic to beclomethasone dipropionate, formoterol fumarate, glycopyrrolate or any of the ingredients in TRIMBOW. See the end of this Patient Information for complete list of ingredients in TRIMBOW. have heart problems. have high blood pressure. have seizures. have thyroid problems. have diabetes. have liver problems. have weak bones (osteoporosis). have an immune system problem. have eye problems such as glaucoma, increased pressure in your eye, cataracts, blurred vision, or other changes in vision. TRIMBOW may make your glaucoma worse. have prostate or bladder problems, or problems passing urine. TRIMBOW may make these problems worse. have any type of viral, bacterial, parasitic, or fungal infection. are exposed to chickenpox or measles. are pregnant or plan to become pregnant. It is not known if TRIMBOW may harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if the medicines in TRIMBOW pass into your breast milk and if they can harm your baby. anticholinergics (including tiotropium, ipratropium, aclidinium) atropine other LABA (including salmeterol, formoterol fumarate, arformoterol, vilanterol, olodaterol, and indacaterol) antifungal or anti-HIV medicines. Do not use TRIMBOW unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly. TRIMBOW comes in different strengths. Your healthcare provider prescribed the strength that is best for you. If you have been using different inhaler containing beclomethasone dipropionate previously, ask your doctor for advice, as the effective dose of beclomethasone dipropionate in TRIMBOW for the treatment of your asthma may be lower than that of some other inhalers. Use TRIMBOW exactly as your healthcare provider tells you to use it. Do not use TRIMBOW more often than prescribed. Use inhalations of TRIMBOW, times each day (2 puffs in the morning and puffs in the evening). If you miss dose of TRIMBOW, take it as soon as you remember. Do not take more than inhalations per day. Take your next dose at your usual time. If you take too much TRIMBOW, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness. Do not use other medicines that contain LABA or an anticholinergic for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA or anticholinergic medicines. Do not stop using TRIMBOW unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed. TRIMBOW does not relieve sudden symptoms of asthma and you should not take extra doses of TRIMBOW to relieve these sudden symptoms. Always have rescue inhaler with you to treat sudden symptoms. If you do not have rescue inhaler, call your healthcare provider to have one prescribed for you. Call your healthcare provider or get medical care right away if: your breathing problems get worse. you need to use your rescue inhaler more often than usual. your rescue inhaler does not work as well to relieve your symptoms. your breathing problems get worse. you need to use your rescue inhaler more often than usual. your rescue inhaler does not work as well to relieve your symptoms. fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using TRIMBOW to help reduce your chance of getting thrush. weakened immune system and increased chance of getting infections (immunosuppression).. reduced adrenal function (adrenal insufficiency). Adrenal insufficiency is condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking medicine containing an ICS (such as TRIMBOW). During this transition period, when your body is under stress from fever, trauma (such as car accident), infection, surgery, or worse asthma symptoms, adrenal insufficiency can get worse and may cause death. sudden breathing problems immediately after inhaling your medicine. If you have sudden breathing problems immediately after inhaling your medicine, stop using TRIMBOW and call your healthcare provider right away. serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of serious allergic reaction: effects on heart.. effects on nervous system.. bone thinning or weakness (osteoporosis).. eye problems including glaucoma, increased pressure in your eye, cataracts, blurred vision, worsening of narrow-angle glaucoma, or other changes in vision. You should have regular eye exams while using TRIMBOW. urinary retention. People who take TRIMBOW may develop new or worse urinary retention. Symptoms of urinary retention may include: changes in laboratory blood values, including high levels of blood sugar (hyperglycemia) and low levels of potassium (hypokalemia). slowed growth in children. itchy, runny or blocked nose sore throat headache bronchitis high blood pressure respiratory tract infection hoarseness or laryngitis flu. back pain inflammation of the nasal lining low red blood cells (anemia) inflammation of the sinuses inflammation of throat muscle spasms pneumonia mouth and throat pain. Prior to first use: Store in refrigerator 36F to 46F (2C to 8C). After first use: Store at room temperature 68F to 77F (20C to 25C) for maximum of months. Throw away TRIMBOW months after you remove from the refrigerator, or when the dose counter reaches zero 0, whichever comes first. Do not put hole in the TRIMBOW canister. Do not throw the canister into fire or incinerator. Do not use or store it near heat or open flame. Temperatures higher than 122F (50C) may cause bursting.

SPL UNCLASSIFIED SECTION.

1.1 Maintenance Treatment of Asthma TRIMBOW is indicated for the maintenance treatment of asthma in patients aged 18 years and older.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Hepatic impairment: formoterol fumarate systemic exposure may increase in patients with severe impairment. Monitor for systemic beta-agonists effects. (8.6, 12.3) 8.1 Pregnancy Risk Summary There are insufficient data on the use of TRIMBOW or its individual components, beclomethasone dipropionate, formoterol fumarate, and glycopyrrolate, in pregnant women to inform drug-associated risk. See Clinical Considerations.) Studies in animals have shown reproductive toxicity. Beclomethasone dipropionate was considered responsible for reproductive toxicity effects in rats such as reduction of the conception rate, fertility index, early embryonic development parameters (implantation loss), delay in ossification and increased incidence of visceral variations. Tocolytic and antimuscarinic effects, attributed to the beta2-adrenergic activity of formoterol fumarate and the antimuscarinic activity of glycopyrrolate, affected pregnant rats in the late phase of gestation and/or early phase of lactation, leading to loss of pups. The estimated risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored, and medication adjusted as necessary to maintain optimal control of asthma. Labor or Delivery:There are no well-controlled human trials that have investigated the effects of TRIMBOW on preterm labor or labor at term. TRIMBOW should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.Infants and neonates born to mothers receiving substantial doses should be observed for adrenal suppression. If treatment during pregnancy is necessary, the lowest effective dose should be used. Data Animal DataThe effects of TRIMBOW on fertility, early embryonic development to implantation and fetal and post-natal development were investigated in rats after oral administration. The reproduction studies determined safe levels in the rat, but also clearly highlighted the known corticosteroid-related effects on maternal and fetal toxicity. No effects on male fertility were seen, but reduced female fertility, embryonic implantation and fetal development were observed from the dose of mg/kg/day (this dose is 18, 37 and 77 times the maximum clinical dose as body surface for BDP, FF and respectively). Furthermore, the contribution of in the observed effects on food consumption, bodyweight and general tolerability by the dams was also significant. For these reasons, the possible benefits of the drug must be weighed against the possible risks during pregnancy. No additional side effects have been observed with respect to the single agents. 8.2 Lactation Risk Summary There is no information available on the presence of beclomethasone dipropionate, formoterol fumarate or glycopyrrolate in human milk; the effects on the breastfed child; or the effects on milk production. Glucocorticoids are excreted in human milk. It is reasonable to assume that beclomethasone dipropionate and its metabolites are also excreted in human milk. It is unknown whether formoterol fumarate or glycopyrrolate (including their metabolites) are excreted in human milk, but they have been detected in the milk of lactating animals. Anticholinergics like glycopyrrolate could suppress lactation. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TRIMBOW and any potential adverse effects on the breast-fed child from TRIMBOW or from the underlying maternal condition. DataAnimal DataThere is no available data on the exposure and effects of TRIMBOW in rat pups. Formoterol FumarateIn the fertility and reproduction study in rats, plasma levels of formoterol were measured in pups on post-natal day 15. It was estimated that the maximum plasma concentration that the pups received from the maternal animal, at the highest dose of 15 mg/kg, after nursing was 4.4% (0.24 nmol/L for litter vs. 5.5 nmol/L for the mother). GlycopyrrolateIn the reproductive/developmental toxicity study in rats, plasma levels of glycopyrrolate were measured in pups on post-natal day 4. The maximum concentration in the pups was 6% of the maternal dose of 10 mg/kg/day (pup plasma concentration of 96 ng/mL at hour after dosing corresponded with 1610 ng/mL in the dam at 0.5 hours after dosing). 8.4 Pediatric Use. The safety and effectiveness of TRIMBOW have not been established in pediatric patients (aged 17 years and younger). TRIMBOW is not indicated for use in pediatric patients.Effects on GrowthOrally inhaled corticosteroids may cause reduction in growth velocity when administered to children and adolescents.Controlled clinical trials have shown that ICS may cause reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately cm/year (range: 0.3 to 1.8 cm/year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown.. 8.5 Geriatric Use. Based on available data, no adjustment of the dosage of TRIMBOW in geriatric patients 65 and above is necessary, but greater sensitivity in some older individuals cannot be ruled out.In Trials and 2, 204 subjects aged 65 years and older, of which subjects were aged 75 years and older, were administered TRIMBOW 100/6/12.5 mcg or TRIMBOW 200/6/12.5 mcg. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between elderly and younger subjects.. 8.6 Hepatic Impairment. TRIMBOW has not been studied in subjects with hepatic impairment. Information on the individual components is provided below. Formal pharmacokinetic studies using TRIMBOW have not been conducted in patients with hepatic impairment. However, since formoterol fumarate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of formoterol fumarate in plasma. Therefore, patients with severe hepatic disease should be closely monitored. Beclomethasone dipropionateThe pharmacokinetics of beclomethasone dipropionate in patients with hepatic impairment have not been studied; however, as beclomethasone dipropionate undergoes very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver, to originate the more polar products beclomethasone 21-monopropionate, beclomethasone 17-monopropionate and beclomethasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclomethasone dipropionate.Glycopyrrolate The pharmacokinetics of glycopyrrolate in patients with hepatic impairment have not been studied, however, as glycopyrrolate is predominantly cleared by renal excretion, hepatic impairment is not thought to result in clinically relevant increase of glycopyrrolate systemic exposure.Formoterol fumarateThe pharmacokinetics of formoterol have not been studied in patients with hepatic impairment; however, as formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.. 8.7 Renal Impairment. TRIMBOW can be used at the recommended dose in patients with mild (glomerular filtration rate [GFR] >=50 to <80 mL/min/1.73 m2) to moderate (GFR >=30 to <50 mL/min/1.73 m2) renal impairment. Use in patients with severe (GFR <30 mL/min/1.73 m2) renal impairment or end-stage renal (GFR <15 mL/min/1.73 m2) disease requiring dialysis, especially if associated with significant body weight reduction, should be considered only if the expected benefit outweighs the potential risk.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. LABA monotherapy increases the risk of serious asthma-related events. (5.1) Do not initiate in acutely deteriorating asthma. Do not use to treat acute symptoms. (5.2) Do not use in combination with additional therapy containing LABA because of risk of overdose. (5.3) Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.4) Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.5) Risk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to TRIMBOW. (5.6) Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue TRIMBOW slowly. (5.7) If paradoxical bronchospasm occurs, discontinue TRIMBOW and institute alternative therapy. (5.9) Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. (5.11) Assess for decrease in bone mineral density initially and periodically thereafter. (5.12) Glaucoma and cataracts may occur with long-term use of ICS. Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact healthcare provider immediately if symptoms occur. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use TRIMBOW long term. (5.13) Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact healthcare provider immediately if symptoms occur. (5.14) Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.15) Be alert to hypokalemia and hyperglycemia. (5.16). LABA monotherapy increases the risk of serious asthma-related events. (5.1) Do not initiate in acutely deteriorating asthma. Do not use to treat acute symptoms. (5.2) Do not use in combination with additional therapy containing LABA because of risk of overdose. (5.3) Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.4) Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.5) Risk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to TRIMBOW. (5.6) Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue TRIMBOW slowly. (5.7) If paradoxical bronchospasm occurs, discontinue TRIMBOW and institute alternative therapy. (5.9) Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. (5.11) Assess for decrease in bone mineral density initially and periodically thereafter. (5.12) Glaucoma and cataracts may occur with long-term use of ICS. Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact healthcare provider immediately if symptoms occur. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use TRIMBOW long term. (5.13) Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact healthcare provider immediately if symptoms occur. (5.14) Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.15) Be alert to hypokalemia and hyperglycemia. (5.16). 5.1 Serious Asthma-Related Events Hospitalizations, Intubations, Death Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta -adrenergic Agonists ).Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic AgonistsFour (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: trial compared budesonide/formoterol fumarate with budesonide, trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, and trial compared mometasone furoate/formoterol fumarate with mometasone furoate. The fourth trial included pediatric subjects aged to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all trials was serious asthma-related events (hospitalizations, intubations, death). blinded adjudication committee determined whether events were asthma related.The adult and adolescent trials were designed to rule out risk margin of 2.0, and the pediatric trial was designed to rule out risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. meta-analysis of the adult and adolescent trials did not show significant increase in risk of serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and OlderICS/LABA (n 17,537)aICS (n 17,552)aICS/LABA vs. ICS Hazard Ratio (95% CI)bSerious asthma-related eventc 1161051.10 (0.85, 1.44)Asthma-related death20 Asthma-related intubation (endotracheal)12Asthma-related hospitalization (>=24-hour stay)115105ICS Inhaled Corticosteroid, LABA Long-acting Beta2-adrenergic Agonist. Randomized subjects who had taken at least dose of study drug. Planned treatment used for analysis. Estimated using Cox proportional hazards model for time to first event with baseline hazards stratified by each of the trials. Number of subjects with event that occurred within months after the first use of study drug or days after the last date of study drug, whichever date was later. Subjects can have or more events, but only the first event was counted for analysis. single, blinded, independent adjudication committee determined whether events were asthma related.The pediatric safety trial included 6,208 pediatric subjects aged to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show significantly increased risk of serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27).TRIMBOW is not indicated for use in pediatric patients aged 17 years and younger.Salmeterol Multicenter Asthma Research Trial (SMART)A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered class effect of LABA monotherapy.. 5.2 Deterioration of Disease and Acute Episodes TRIMBOW should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. TRIMBOW has not been studied in subjects with acutely deteriorating asthma. The initiation of TRIMBOW in this setting is not appropriate. Increasing use of inhaled, short-acting beta2-agonists is marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than inhalations twice daily of TRIMBOW.TRIMBOW should not be used for the relief of acute symptoms (i.e., as rescue therapy for the treatment of acute episodes of bronchospasm). TRIMBOW has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. When beginning treatment with TRIMBOW, patients who have been taking oral or inhaled, short-acting beta2-agonists on regular basis (e.g., times day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing TRIMBOW, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.. 5.3 Avoid Excessive Use of TR IMBOW and Avoid Use with Other Long- acting Beta - agonists TRIMBOW should not be used more often than recommended, at higher doses than recommended, or in conjunction with other therapies containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using TRIMBOW should not use another therapy containing LABA (e.g., salmeterol, formoterol fumarate, arformoterol, vilanterol, olodaterol or indacaterol) for any reason. 5.4 Oropharyngeal Candi diasis TRIMBOW contains beclomethasone dipropionate, an ICS. Localized infections of the mouth and pharynx with Candida albicans have occurred in subjects treated with orally inhaled drug products containing beclomethasone dipropionate. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with TRIMBOW continues. In some cases, therapy with TRIMBOW may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of TRIMBOW to help reduce the risk of oropharyngeal candidiasis.. 5.5 Immunosuppression and Risk of Infections Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles can have more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing disseminated infection is not known. The safety and effectiveness of TRIMBOW have not been established in pediatric patients and TRIMBOW is not indicated for use in this population. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered.ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.. 5.6 Transferring Patients from Systemic Corticosteroid Therapy HPA Suppression/Adrenal InsufficiencyParticular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although TRIMBOW may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.During periods of stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their health care practitioner for further instruction. These patients should also be instructed to carry warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack.Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to TRIMBOW. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on weekly basis during therapy with TRIMBOW. Lung function (FEV1), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Unmasking of Allergic Conditions Previously Suppressed by Systemic CorticosteroidsTransfer of patients from systemic corticosteroid therapy to TRIMBOW may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Corticosteroid Withdrawal SymptomsDuring withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.. 5.7 Hypercorticism and Adrenal Suppression Inhaled beclomethasone dipropionate is absorbed into the circulation and can be systemically active. Effects of beclomethasone dipropionate on the HPA axis are not observed with the therapeutic doses of beclomethasone dipropionate in TRIMBOW. However, exceeding the recommended dosage or coadministration with strong cytochrome P450 3A (CYP3A4 and CYP3A5) inhibitor may result in HPA dysfunction [see Warnings and Precautions 5.8 ), Drug Interactions 7.1 )]. Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with TRIMBOW should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in small number of patients who are sensitive to these effects. If such effects occur, reduce the dose of TRIMBOW slowly, consistent with accepted procedures for reducing systemic corticosteroids, and consider other treatments for management of asthma symptoms.. 5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of TRIMBOW with ketoconazole and other known strong CYP3A4 inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions 7.1 ), Clinical Pharmacology 12.3 )]. 5.9 Paradoxical Bronchospasm As with other inhaled therapies, TRIMBOW can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with TRIMBOW, it should be treated immediately with an inhaled, short-acting bronchodilator; TRIMBOW should be discontinued immediately; and alternative therapy should be instituted. 5.10 Hypersensitivity Reactions, including Anaphylaxis Hypersensitivity reactions have been reported after administration of beclomethasone dipropionate, formoterol fumarate or glycopyrrolate, the components of TRIMBOW. 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, TRIMBOW should be discontinued immediately, and alternative therapy instituted [see Contraindications 4 )] . 5.11 Cardiovascular ffects Formoterol fumarate, like other beta2-agonists, can produce clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles.If such effects occur, TRIMBOW may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown [see Clinical Pharmacology 12.2 )]. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Therefore, TRIMBOW should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.. 5.12 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. 5.13 Glaucoma and Cataracts, Worsening of Narrow-Angle Glaucoma Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of ICS or with use of inhaled anticholinergics. TRIMBOW should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should also be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult healthcare provider immediately if any of these signs or symptoms develop. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use TRIMBOW long term.. 5.14 Worsening of Urinary Retention TRIMBOW, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult healthcare provider immediately if any of these signs or symptoms develop.. 5.15 Coexisting Conditions TRIMBOW, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.. 5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist therapies may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist therapies may produce transient hyperglycemia in some patients.. 5.17 Effect on Growth Orally inhaled corticosteroids may cause reduction in growth velocity when administered to children and adolescents. The safety and effectiveness of TRIMBOW have not been established in pediatric patients (aged 17 years and younger) and TRIMBOW is not indicated for use in this population s ee Use in Specific Populations 8.4 ].