Palpitations Nausea Hypersensitivity Depression Agitation Restlessness Nervousness Tremor Dizziness Angina pectoris Tachycardia Arrhythmias (eg, atrial fibrillation, supraventricular tachycardia, extrasystoles) Throat irritation Bronchospasm Dry mouth Bruising Urinary retention Chest pain Sign or symptoms of systemic glucocorticoid steroid effects (eg, hypofunctional adrenal gland) Abnormal behavior Contraindications Hypersensitivity Cautions Safety and efficacy not established for asthma; use of long-acting beta2-adrenergic agonists (LABAs) as monotherapy (ie, without inhaled corticosteroids) for asthma is associated with increased risk asthma-related death; data do not suggest an increased risk of death with LABAs in patients with COPD Do not initiate in patients with acutely deteriorating COPD, which may be a life-threatening condition; use only for maintenance and not as a rescue therapy Patients who have been taking inhaled, short-acting beta2 agonists on a regular basis should discontinue these drugs when budesonide/formoterol/glycopyrrolate inhaled is initiated Excess use or use with other long-acting beta2 agonists may result in overdose, clinically significant cardiovascular effects, and fatalities Oropharyngeal candidiasis is associated with orally inhaled corticosteroids; advised patients to rinse mouth with water and without swallowing Lower respiratory tract infections, including pneumonia, reported following inhaled corticosteroids Immunosuppressive drugs (eg, corticosteroids) use increases susceptibility to infection; some infections may be more serious or fatal compared with others not taking corticosteroids Caution if patients are being transferred from systemic corticosteroids; monitor for adrenal insufficiency, particularly for patients maintained on physiologic doses (eg, ≥20 mg/day of prednisone, or equivalent) Hypercorticism and adrenal suppression may occur if dose is exceeded Oral inhaled therapies can produce paradoxical bronchospasm, which may be life-threatening; if this occurs, permanently discontinue and treat immediately with inhaled, short-acting bronchodilator Hypersensitivity, including anaphylaxis, reported; allergic reactions including angioedema, urticaria, or rash may occur; discontinue drug Beta2 agonists can produce clinically significant cardiovascular effects (eg, increased heart rate and blood pressure, arrhythmias, ECG changes) Decreased bone mineral density observed with long-term administration of corticosteroids Use of long-term corticosteroids or inhaled anticholinergics associated with glaucoma, cataracts, or worsening of narrow-angle glaucoma Caution in patients with urinary retention (eg, prostatic hyperplasia, bladder-neck obstruction) Caution with sympathomimetic use in patients with convulsive disorders or thyrotoxicosis; beta2 agonists may aggravate preexisting diabetes mellitus and ketoacidosis Beta agonists may produce significant hypokalemia and transient hyperglycemia Drug interaction overview Strong CYP3A4 inhibitors Exercise caution Coadministration with strong CYP3A4 inhibitors may increase budesonide systemic exposure Adrenergic drugs Exercise caution Coadministration of formoterol with other adrenergic drugs may cause additive sympathetic effects Xanthine derivatives, corticosteroids, or diuretics Monitor for hypokalemia Coadministration of beta2 agonists (eg, formoterol) with xanthine derivatives, corticosteroids, or diuretics may potentiate risk of hypokalemia The hypokalemia and/or ECG changes that may result from nonpotassium sparing diuretics may be worsened by beta2 agonists, especially if beta2 agonist dose exceeded MAOIs, TCAs, or QTc prolonging drugs Use extreme caution with beta2 agonists in patients treated with MAOIs, TCAs, or other drugs known to prolong QTc interval owing to additive action of adrenergic agonists on the cardiovascular system Beta blockers Beta blockers inhibit the therapeutic effect of beta2 agonists and may also produce severe bronchospasm Patients with COPD should normally not use beta blockers, excepts under certain circumstances (eg, prophylaxis after MI); consider cardioselective beta blockers when necessary Anticholinergics Monitor Coadministration of glycopyrrolate with anticholinergic medications may cause additive effects Pregnancy Data are not available for glycopyrrolate or formoterol fumarate in pregnant women; however, studies are available for budesonide Studies (Swedish registries) of pregnant women who received inhaled budesonide alone during pregnancy did not show increased risk of abnormalities Clinical considerations Labor or delivery: No well-controlled human trials; because of potential for beta agonists interfering with uterine contractility, restrict use during labor to patients in whom benefits clearly outweigh risks Animal studies Budesonide SC administration caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at 0.3 and 0.75 times the maximum recommended human daily inhaled dose (MRHDID), but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID Experience with PO corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans Formoterol Oral administration in rats and rabbits caused structural abnormalities at 1,500 and 61,000 times the MRHDID It was also embryocidal, increased pup lost at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID No structural abnormalities, embryocidal, or developmental effects observed in rats that received inhalation doses up to 350 times the MRHDID Glycopyrrolate SC administration in rats and rabbits did not cause structural abnormalities or affect fetal survival at 2,700-5,400 times MRHDID It also had no effects on physical, functional, and behavioral development of rat pups up to 2,700 times the MRHDID Lactation Data are not available for glycopyrrolate or formoterol fumarate in lactating women; however, studies are available for budesonide Budesonide dry powder inhalation shows the total daily oral dose of budesonide available in breast milk to the infant is ~0.3-1% of the maternal inhaled dosePregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Budesonide: Anti-inflammatory corticosteroid; has potent glucocorticoid activity and weak mineralocorticoid activity Formoterol: Long-acting selective beta-2 agonist with rapid onset of action; acts locally as bronchodilator; stimulates intracellular adenyl cyclase, which results in increased cyclic adenosine monophosphate levels, causing relaxation of bronchial smooth muscle and inhibition of release of mast cell mediators Glycopyrrolate: Long-acting muscarinic antagonist; often referred to as an anticholinergic; produces bronchodilation by inhibiting acetylcholine’s effect on muscarinic receptors in the airway smooth muscle Absorption Peak plasma time Budesonide: 20-40 minutes Formoterol: 20-60 minutes Glycopyrrolate: 2-6 minutes Steady-state Budesonide: 1 day Formoterol: 2 days Glycopyrrolate: 3 days Distribution Protein bound Budesonide: 86-87% Formoterol: 46-58% Glycopyrrolate: 43-54% Vd Budesonide: 1,200 L Formoterol: 2,400 L Glycopyrrolate: 5,500 L Metabolism Budesonide: Extensively metabolized in liver by CYP3A4 Formoterol: Primarily metabolized by direct glucuronidation and by O-demethylation (by CYP2D6 and CYP2C) followed by conjugation to inactive metabolites; secondary metabolism by deformylation and sulfate Glycopyrrolate: Metabolism plays a minor role in the overall elimination; CYP2D6 found to be the predominant enzyme involved Elimination Half-life Budesonide: ~5 hr Formoterol: ~10 hr Glycopyrrolate: ~15 hr Excretion Budesonide: Excreted in urine and feces as metabolites; negligible unchanged drug detected in urine Formoterol: Urine 62%; feces 24% Glycopyrrolate: Urine 85%; also small amount in bile Inhalation Preparation Priming canister First use: Prime canister by releasing 4 sprays into the air when first administered Inhaler not used for >7 days or after cleaning: Prime canister by releasing 2 sprays into the air Dose indicator Canister has dose indicator showing how many inhalations remain Display moves after every tenth actuation Color behind dose indicator changes to red when nearing end of usable inhalations Inhalation Administration Shake well before oral inhalation Exhale fully through mouth, close lips around mouthpiece and tilt head back, keeping tongue below the mouthpiece, while breathing in deeply and slowly, release puff of medication by pressing on actuator; repeat for second inhalation Rinse mouth with water and spit out water after each dose (2 inhalations) to reduce risk of thrush Avoid spraying in eyes Missed dose Take missed dose as soon as possible and the next dose at the usual time Do not take more than 1 dose to make up for a missed dose Storage Store at controlled room temperature of 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF) Keep in dry place away from heat and sunlight Contents under pressure; do not puncture or store near heat or open flame Exposure to temperature >49ºC (>120ºF) may cause bursting Never throw canister into fire or incinerator No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the lowest co-pay. 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