Trimbow

1 INDICATIONS AND USAGE TRIMBOW is indicated for the maintenance treatment of asthma in adult patients aged 18 years and older. Limitati ons of Use TRIMBOW is NOT indicated for relief of acute bronchospasm [see Warnings and Precautions ( 5.2 ) ] . TRIMBOW is a combination of beclomethasone dipropionate (BDP) (an inhaled corticosteroid [ICS]), formoterol fumarate (FF) (a long-acting beta 2 -adrenergic agonist [LABA]), and glycopyrrolate (G) (an anticholinergic) indicated for the maintenance treatment of asthma in adult patients aged 18 years and older. ( 1 ) Limitation s of Use Not indicated for relief of acute bronchospasm. ( 1 )

2 DOSAGE AND ADMINISTRATION For oral inhalation only. ( 2.1 ) Prime TRIMBOW before first time use and re-prime if not used for 30 days or longer. ( 2.1 ) Recommended Dosage : TRIMBOW 172 mcg/9.8 mcg/21.2 mcg (administered as 2 actuations of beclomethasone dipropionate 86 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg) twice daily by oral inhalation or TRIMBOW 344 mcg/9.8 mcg/21.2 mcg (administered as 2 actuations of beclomethasone dipropionate 172 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg) twice daily by oral inhalation. ( 2.2 ) 2.1 Preparation and Admini stration Information Administer TRIMBOW by oral inhalation. After inhalation, rinse the mouth with water without swallowing it to help reduce the risk of oropharyngeal candidiasis [see Warnings and Precautions ( 5.4 )] . Priming Before Use Prime TRIMBOW by actuating 2 times prior to using the first dose from a new canister. Re-prime if the inhaler has not been used for 30 days or longer . Dose Counter TRIMBOW has a dose counter attached to the canister. The counter starts at 122 and counts down each time a 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 2 months have passed since first use date, whichever comes first. 2.2 Recommen d ed Dosage The recommended dosage of: TRIMBOW is beclomethasone dipropionate 172 mcg, formoterol fumarate 9.8 mcg, and glycopyrrolate 21.2 mcg (administered as 2 actuations of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 86 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg]) twice daily (in the morning and evening) by oral inhalation. or TRIMBOW is beclomethasone dipropionate 344 mcg, formoterol fumarate 9.8 mcg, and glycopyrrolate 21.2 mcg (administered as 2 actuations of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 172 mcg, formoterol fumarate 4.9 mcg, glycopyrrolate 10.6 mcg]) twice daily (in the morning and evening) by oral inhalation The recommended starting dosage for TRIMBOW is based upon patients' asthma severity or level of control of asthma symptoms on current inhaled corticosteroids. For patients who do not respond adequately to a starting dose of TRIMBOW 172 mcg/9.8 mcg/21.2 mcg (2 actuations of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 86 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg]) twice daily, additional asthma control may be provided by replacement with a dose of TRIMBOW 344 mcg/9.8 mcg/21.2 mcg (2 actuations of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 344 mcg, formoterol fumarate 9.8 mcg, and glycopyrrolate 21.2 mcg]) twice daily. For patients who do not respond adequately to a dose of TRIMBOW 344 mcg/9.8 mcg/21.2 mcg twice daily, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered. The maximum recommended dosage is TRIMBOW 344 mcg/9.8 mcg/21.2 mcg (2 actuations of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 344 mcg, formoterol fumarate 9.8 mcg, and glycopyrrolate 21.2 mcg]) twice daily by oral inhalation. Do not take more than two oral inhalations twice daily.

3 DOSAGE FORMS AND STRENGTHS Inhalation aerosol: a pressurized metered dose inhaler that delivers a combination of 86 mcg/4.9 mcg/10.6 mcg (beclomethasone dipropionate 86 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg) per actuation. Inhaler supplied with a grey plastic actuator, dose counter, grey mouthpiece and red cap. 172 mcg/4.9 mcg/10.6 mcg (beclomethasone dipropionate 172 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg) per actuation. Inhaler supplied with grey plastic actuator, dose counter, grey mouthpiece and green cap. Inhalation aerosol: 86 mcg/4.9 mcg/10.6 mcg (beclomethasone dipropionate 86 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg) per actuation. ( 3 ) 172 mcg/4.9 mcg/10.6 mcg (beclomethasone dipropionate 172 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg) per actuation. ( 3 )

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 ( 5.9 ) and Description ( 11 )] . Primary treatment of status asthmaticus or asthma requiring intensive measures. ( 4 ) Severe hypersensitivity to any of the ingredients. ( 4 )

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 ( 5.8 )] Cardiovascular Effects [ see Warnings and Precautions ( 5.10 )] Reduction in Bone Mineral Density [ see Warnings and Precautions ( 5.11 )] Worsening of Narrow-Angle Glaucoma [ see Warnings and Precautions ( 5.12 )] Worsening of Urinary Retention [ see Warnings and Precautions ( 5.13 ) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most common adverse reactions (incidence ≥ 1%) are bronchitis, hypertension, back pain, blood pressure increased, dysphonia, upper respiratory tract infection, influenza, anemia, muscle spasms, laryngitis, oropharyngeal pain, and sinusitis. ( 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 (TRIMARAN and TRIGGER) that included 2,294 adult patients with asthma who received TRIMBOW or BDP/FF comparator [ see Clinical Studies ( 14 ) ] . The incidence of adverse reactions occurring in ≥1% of the patients treated with a dose of TRIMBOW 172 mcg/9.8 mcg/21.2 mcg or a dose of TRIMBOW 344 mcg/9.8 mcg/21.2 mcg, both doses at twice daily by oral inhalation, is shown in Table 2. Table 2. Adverse Reactions with TRIMBOW with ≥1% Incidence and Greater than Active Control in Adult Patients with Asthma in the TRIMARAN and TRIGGER 52-week Trials Adverse Reactions in TRIMARAN ( n , %) TRIMBOW 172 mcg / 9.8 mcg /2 1. 2 mcg twice daily (N = 576) BDP/FF 172 mcg / 9.8 mcg twice daily (N = 574) Hypertension 16 (3) 9 (2) Blood pressure increased 12 (2) 7 (1) Dysphonia 11 (2) 3 (<1) Upper respiratory tract infection 11 (2) 10 (2) Influenza 9 (2) 7 (1) Anemia 8 (1) 5 (1) Adverse Reactions in TRIGGER ( n , %) TRIMBOW 344 mcg / 9.8 mcg /2 1. 2 mcg twice daily (N = 571) BDP/FF 344 mcg / 9.8 mcg twice daily (N = 57 3 ) Bronchitis 18 (3) 18 (3) Back pain 12 (2) 5 (1) Dysphonia 11 (2) 9 (2) Hypertension 10 (2) 7 (1) Influenza 7 (1) 6 (1) Muscle spasms 6 (1) 6 (1) Laryngitis 6 (1) 3 (<1) Oropharyngeal pain 6 (1) 3 (<1) Sinusitis 6 (1) 3 (<1) Abbreviations: BDP, beclomethasone dipropionate; FF, formoterol fumarate; N, number of patients

7 DRUG INTERACTIONS Other adrenergic drugs may potentiate effect: Use with caution. ( 7.1 ) Diuretics, xanthine derivatives or steroids may potentiate hypokalemia or ECG changes. Use with caution. ( 7.2 ) Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. ( 7.3 ) Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.4 ) Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of TRIMBOW with other anticholinergic-containing drugs. ( 7.6 ) 7. 1 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, a component of TRIMBOW, may be potentiated [see Warnings and Precautions ( 5.3 )] . 7. 2 Xanthine Derivatives, Steroids, or Diuretics Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate the hypokalemic effect of beta 2 -adrenergic agonists such as formoterol fumarate, a component of TRIMBOW. 7. 3 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and QTc Prolonging Drugs Formoterol, as with other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides or drugs known to prolong the QTc interval because the action 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. 4 Beta-adre ner gic Receptor Blocking Agents Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta2-agonists, such as formoterol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. 7. 5 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. 7. 6 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 ( 5.12 , 5.13 )] .

8 USE IN SPECIFIC POPULATIONS Hepatic impairment: formoterol fumarate systemic exposure may increase in patients with severe hepatic impairment. Monitor for systemic beta-agonists effects. ( 8.6 , 12.3 ) Renal impairment: In patients with severe renal impairment, use should be considered only if the potential benefit of the treatment outweighs the risk ( 8.7 ). 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with TRIMBOW or its individual components, beclomethasone dipropionate, formoterol fumarate, and glycopyrrolate in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (See Clinical Considerations ) . In animal reproduction studies, beclomethasone dipropionate (BDP) resulted in adverse developmental effects in mice and rabbits at subcutaneous doses equal to or greater than approximately 0.6 times the maximum recommended human daily inhalation dose (MRHDID) in adults (800 mcg/day) [see Data ] . In rats exposed to beclomethasone dipropionate by inhalation, dose-related gross injury to the fetal adrenal glands was observed at doses greater than 140 times the MRHDID, but there was no evidence of external or skeletal malformations or embryolethality at inhalation doses of up to 350 times the MRHDID. In animal reproduction studies, formoterol fumarate (FF) produced malformations that included umbilical hernia and brachygnathia (a skeletal malformation) in rats at oral doses 1,200 and 6,100 times the MRHDID in adults, respectively. In rabbits, formoterol fumarate produced subcapsular cysts on the liver at oral doses 49,000 times the MRHDID in adults. In rats exposed to formoterol fumarate by inhalation, no teratogenic effects were observed at 500 times the MRHDID in adults. Glycopyrrolate (G) administered by the oral route in rats and rabbits did not cause structural abnormalities or affect fetal survival at exposures approximately 179 and 50 times MRHDID, respectively. TRIMBOW administered by the oral route in rats caused reduction in fetal weights and increased incidence of visceral variations at doses 83 and 0.8 times the MRHDID and higher for BDP (metabolite- B17MP) and FF, respectively. TRIMBOW also caused decreased pup survival, increase in post-implantation loss and reduced mean litter size in rats at 1.9, 3.7, and 7.7 times the MRHDID (based on a mg/m 2 ) for BDP, FF, and G, respectively. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. 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 Data Beclomethasone dipropionate (BDP) In an embryofetal development study in pregnant rats, beclomethasone dipropionate administration during organogenesis from gestation days 6 to 15 at inhaled doses 140 times the MRHDID in a …

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, a long-acting beta 2 -adrenergic agonist and an anticholinergic) that have different effects on clinical physiology. Beclomethasone Dipropionate Beclomethasone dipropionate is a 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 a 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 a binding affinity for the human glucocorticoid receptor, which is approximately 13 times that of dexamethasone, 6 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. Formoterol Fumarate Formoterol fumarate is a long-acting selective beta 2 -adrenergic agonist (beta 2 -agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol fumarate has more than 200-fold greater agonist activity at beta 2 -receptors than at beta 1 -receptors. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -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 beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -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 a 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 a site-specific effect.

11 DESCRIPTION TRIMBOW (beclomethasone dipropionate, formoterol fumarate and glycopyrrolate) Inhalation Aerosol is a pressurized metered-dose inhaler that delivers a combination of beclomethasone dipropionate [an inhaled corticosteroid (ICS)], formoterol fumarate [an inhaled long-acting beta 2 -adrenergic agonist (a LABA)] and 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. Beclomethasone dipropionate is a white to creamy white, odorless powder, insoluble in water, freely soluble in acetone, and sparingly soluble in alcohol, with a molecular weight of 521.04218 g/mol, and the molecular formula is C 28 H 37 ClO 7 . The structural formula is as follows: Formoterol fumarate, a long-acting β2 agonist has the chemical name (E)-but-2-enedioic acid; N -[2-hydroxy-5-[(1 R )-1-hydroxy-2-[[(1 R )-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-formamide dihydrate. Formoterol fumarate is a powder that is slightly soluble in water. Formoterol fumarate has a molecular weight of 840.91 g/mol, and the molecular formula is C 42 H 52 N 4 O 12 . The structural formula is as follows: Formoterol fumarate contains two chiral centers and consists of a single enantiomeric pair (a racemate of R,R and S,S) . Glycopyrrolate is a quarternary ammonium bromide salt with the following chemical name: [ RS- ]-3-[( SR )-(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-Pyrrolidinium bromide. Two asymmetric atoms of carbon are present in the molecule: Glycopyrronium bromide is represented by the (R,S)-(S,R) racemic pair of enantiomers, corresponding to the threo diastereoisomeric structure. Glycopyrrolate is a powder that is freely soluble in water. Glycopyrrolate has a molecular weight of 398.33 g/mol, and the molecular formula is C 19 H 28 BrNO 3 . The structural formula is as follows: Glycopyrrolate contains two chiral centers and is a racemate of a 1;1 mixture of the R,S and S,R diastereomers. The active moiety, glycopyrronium, is the positively charged ion of glycopyrrolate. TRIMBOW 86 mcg/4.9 mcg/10.6 mcg and TRIMBOW 172 mcg/4.9 mcg/10.6 mcg are formulated as a hydrofluoroalkane (HFA 134a) propelled pressurized, metered-dose inhalers, each containing 120 actuations. The canister is supplied with a grey plastic actuator with an integrated dose counter mechanism and mouthpiece, and a red cap (TRIMBOW 86 mcg/4.9 mcg/10.6 mcg) or a green cap (TRIMBOW 172 mcg/4.9 mcg/10.6 mcg). As a solution, TRIMBOW does not need to be shaken before use. TRIMBOW should be “primed” by actuating 2 times prior to using the first dose from a new canister. If the inhaler has not been used for 30 days or longer, re-prime the inhaler [ see How Supplied/Storage and Handling ( 16 ) ] . After priming, each actuation meters 100 or 200 mcg of beclomethasone dipropionate, 6.0 mcg of formoterol fumarate (equivalent to 5.7 mcg of formoterol fumarate anhydrous), and 12.5 mcg of glycopyrrolate (equivalent to 10 mcg of glycopyrronium) in 73.8 mg of solution from the valve and delivers 86 or 172 mcg of beclomethasone dipropionate, 4.9 mcg of formoterol fumarate (equivalent to 4.2 mcg of formoterol fumarate anhydrous), and 10.6 mcg of glycopyrrolate (equivalent to 8.5 mcg of glycopyrronium) from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as coordination of the device (metered dose inhaler [MDI]) actuation with the inhalation maneuver, inspiratory flow and peak inspiratory flow through the delivery system, which may vary in patients with asthma and other pulmonary diseases and conditions. Avoid spraying in the eyes or face while using TRIMBOW. TRIMBOW contains dehydrated alcohol (18% v/v), HFA 134a, and hydrochloric acid as excipients in the formulation. The struct …

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 a 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 Dipropionate If used at excessive doses for prolonged periods, systemic corticosteroid effects, such as hypercorticism may occur [ see Warnings and Precautions ( 5.7 ) ] . Formoterol Fumarate The signs and symptoms with overdosage of formoterol fumarate are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms: angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, and insomnia. Metabolic acidosis may also occur. Cardiac arrest and even death may be associated with an overdose of formoterol fumarate. Glycopyrrolate High doses of glycopyrrolate, a 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.

16 HOW SUPPLIED/STORAGE AND HANDLING TRIMBOW (beclomethasone dipropionate/formoterol fumarate/glycopyrrolate) Inhalation Aerosol: TRIMBOW 86 mcg/4.9 mcg/10.6 mcg: is supplied as a pressurized aluminum container, a grey plastic actuator with the dose counter on the back, a grey mouthpiece and a red cap. TRIMBOW 172 mcg/4.9 mcg/10.6 mcg: is supplied as a pressurized aluminum container, a grey plastic actuator with the dose counter on the back, a grey mouthpiece and a green cap. Each pressurized container of TRIMBOW is packaged in a carton containing one canister, one actuator, a Patient Information leaflet, and the Instructions for Use. TRIMBOW is available as presented in Table 4. Table 4 Package Information for TRIMBOW Strength ( beclomethasone dipropionate/formoterol fumarate/glycopyrrolate) Number of Actuations per Canister Net Fill Weight NDC 86 mcg/4.9 mcg/10.6 mcg 120 11.8 grams NDC 10122-120-02 172 mcg/4.9 mcg/10.6 mcg 120 11.8 grams NDC 10122-121-02 The TRIMBOW container should only be used with the TRIMBOW actuator, and the TRIMBOW actuator should not be used with any other inhalation drug product. Prime the inhaler according to Instructions for Use . If the inhaler has not been used for 30 days or longer, re-prime the inhaler by releasing 2 actuations (puffs) into the air, away from the face and eyes, before use. Dose Counter TRIMBOW has a dose counter attached to the canister. The counter starts at 122 and counts down each time a 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 2 months have passed since first use date, whichever comes first. Contents under Pressure Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 122°F 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 refrigerated at 36°F to 46°F (2°C to 8°C). After first use: Store the inhaler below 77°F (25°C) for a maximum of two months. Do not freeze. Do not expose to temperatures higher than 122°F (50°C) as this may cause bursting.