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Budesonide, Glycopyrrolate, And Formoterol Fumarate

FDA Drug Information • Also known as: Breztri

Brand Names
Breztri
Drug Class
Corticosteroid [EPC], beta2-Adrenergic Agonist [EPC]
Route
RESPIRATORY (INHALATION)
Dosage Form
AEROSOL, METERED
Product Type
HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION BREZTRI AEROSPHERE (budesonide, glycopyrrolate and formoterol fumarate) Inhalation Aerosol is a pressurized metered-dose inhaler that delivers a combination of micronized budesonide [an inhaled corticosteroid (ICS)], micronized glycopyrrolate (an anticholinergic), and micronized formoterol fumarate [an inhaled long-acting beta 2 -adrenergic agonist (a LABA)] for oral inhalation. Budesonide is a corticosteroid with the following chemical name: (RS)-11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is a white to off-white, powder which is practically insoluble in water. The molecular formula is C 25 H 34 O 6 and the molecular weight is 430.54. The structural formula is as follows: Budesonide contains nine chiral centers and is a mixture of the two epimers (22R and 22S). Glycopyrrolate is a quaternary ammonium salt with the following chemical name: (RS)-[3-(SR)-Hydroxy-1,1-dimethylpyrrolidinium bromide] α-cyclopentylmandelate. Glycopyrrolate is a powder that is freely soluble in water. The molecular formula is C 19 H 28 BrNO 3 , and the molecular weight is 398.33 g/mol. 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. Formoterol fumarate has the chemical name N-[2-Hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino] ethyl]phenyl] formamide, (E)-2-butenedioate dihydrate. Formoterol fumarate is a powder that is slightly soluble in water. The molecular formula is (C 19 H 24 N 2 O 4 ) 2 ·C 4 H 4 O 4 ·2H 2 O and the molecular weight is 840.91 g/mol. 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). BREZTRI AEROSPHERE is formulated as a hydrofluoroalkane (HFA 134a) propelled pressurized...

What Is Budesonide, Glycopyrrolate, And Formoterol Fumarate Used For?

1 INDICATIONS AND USAGE BREZTRI AEROSPHERE is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use: BREZTRI AEROSPHERE is not indicated for the relief of acute bronchospasm or for the treatment of asthma [see Warnings and Precautions (5.1 , 5.2) ] . BREZTRI AEROSPHERE is a combination of budesonide, an inhaled corticosteroid (ICS); glycopyrrolate, an anticholinergic; and formoterol fumarate, a long-acting beta 2 -adrenergic agonist (LABA), indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). (1) Limitations of Use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma. (1 , 5.1 , 5.2)

Dosage and Administration

2 DOSAGE AND ADMINISTRATION

  • For oral inhalation only. (2)
  • Maintenance treatment of COPD: 2 inhalations of BREZTRI AEROSPHERE twice daily administered by oral inhalation. (2) 2.1 Recommended Dosage and Administration The recommended dosage of BREZTRI AEROSPHERE is budesonide 320 mcg, glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg (administered as 2 inhalations of BREZTRI AEROSPHERE [budesonide/glycopyrrolate/formoterol fumarate 160 mcg/9 mcg/4.8 mcg]) twice daily, in the morning and in the evening, by oral inhalation. Do not take more than two inhalations twice daily. After inhalation, rinse mouth with water without swallowing. 2.2 Preparation Prime BREZTRI AEROSPHERE before using for the first time. Priming BREZTRI AEROSPHERE is essential to ensure appropriate drug content in each actuation. Prime BREZTRI AEROSPHERE by releasing 4 sprays into the air away from the face, shaking well before each spray. If the inhaler has not been used for more than 7 days, is dropped, or after weekly rinsing, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well before each spray. 2.3 Dose counter BREZTRI AEROSPHERE canister has an attached dose indicator (also known as puff indicator), which indicates how many inhalations (puffs) remain. The dose indicator display has a pointer which will move after every actuation. When nearing the end of the usable inhalations, the pointer is in the yellow zone. BREZTRI AEROSPHERE should be discarded when the pointer is at zero which is in the red zone. 2.1 Recommended Dosage and Administration The recommended dosage of BREZTRI AEROSPHERE is budesonide 320 mcg, glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg (administered as 2 inhalations of BREZTRI AEROSPHERE [budesonide/glycopyrrolate/formoterol fumarate 160 mcg/9 mcg/4.8 mcg]) twice daily, in the morning and in the evening, by oral inhalation. Do not take more than two inhalations twice daily. After inhalation, rinse mouth with water without swallowing. 2.2 Preparation Prime BREZTRI AEROSPHERE before using for the first time. Priming BREZTRI AEROSPHERE is essential to ensure appropriate drug content in each actuation. Prime BREZTRI AEROSPHERE by releasing 4 sprays into the air away from the face, shaking well before each spray. If the inhaler has not been used for more than 7 days, is dropped, or after weekly rinsing, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well before each spray. 2.3 Dose counter BREZTRI AEROSPHERE canister has an attached dose indicator (also known as puff indicator), which indicates how many inhalations (puffs) remain. The dose indicator display has a pointer which will move after every actuation. When nearing the end of the usable inhalations, the pointer is in the yellow zone. BREZTRI AEROSPHERE should be discarded when the pointer is at zero which is in the red zone.

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling.

  • Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions (5.1) ]
  • Oropharyngeal candidiasis infection [see Warnings and Precautions (5.4) ]
  • Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5) ]
  • Immunosuppression and risk of infections [see Warnings and Precautions (5.6) ]
  • Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8) ]
  • Paradoxical bronchospasm [see Warnings and Precautions (5.10) ]
  • Hypersensitivity reactions including anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.11) ]
  • Cardiovascular effects [see Warnings and Precautions (5.12) ]
  • Reduction in bone mineral density [see Warnings and Precautions (5.13) ]
  • Worsening of narrow-angle glaucoma and cataracts [see Warnings and Precautions (5.14) ]
  • Worsening of urinary retention [see Warnings and Precautions (5.15) ] Most common adverse reactions (incidence ≥ 2%) are upper respiratory tract infection, pneumonia, back pain, oral candidiasis, influenza, muscle spasm, urinary tract infection, cough, sinusitis and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. The safety of BREZTRI AEROSPHERE is based on the safety data from one 52-week exacerbation trial (Trial 1) and one 24-week lung function trial with a 28-week safety extension study, resulting in up to 52 weeks of treatment (Trial 2). In Trials 1 and 2, a total of 2783 subjects have received at least 1 dose of BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg [see Clinical Studies (14) ]. In Trials 1 and 2, subjects received one of the following treatments: BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, glycopyrrolate and formoterol fumarate [GFF MDI 18 mcg/9.6 mcg], or budesonide and formoterol fumarate [BFF MDI 320 mcg/9.6 mcg]. Each treatment was administered twice daily. In Trial 1, a 52-week, randomized, double-blind clinical trial, a total of 2144 subjects with COPD received at least 1 dose of BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (mean age: 64.7 years, 84.9% Caucasian, 59.7% male across all treatments) [see Clinical Studies (14) ] . In Trial 2, a 24-week, randomized, double-blind clinical trial, with a 28-week long-term safety extension resulting in up to 52 weeks of treatment, a total of 639 subjects received at least 1 dose of BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (mean age: 65.2 years, 50.1% Caucasian, 71.2% male across all treatments) [see Clinical Studies (14) ] . The incidence of adverse reactions from the 52-week trial (Trial 1) is presented in Table 1 for subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, GFF MDI 18 mcg/9.6 mcg, or BFF MDI 320 mcg/9.6 mcg. Table 1: Adverse reactions occurring at an incidence of ≥ 2% of subjects and more common in BREZTRI AEROSPHERE compared to GFF MDI and/or BFF MDI (Trial 1) Adverse Reaction BREZTRI AEROSPHERE BREZTRI AEROSPHERE = budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg; GFF MDI = glycopyrrolate/formoterol fumarate 18 mcg/9.6 mcg; BFF MDI = budesonide/formoterol fumarate 320 mcg/9.6 mcg; all treatments were administered twice daily. 320 mcg/18 mcg/9.6 mcg N=2144 (%) GFF MDI 18 mcg/9.6 mcg N=2125 (%) BFF MDI 320 mcg/9.6 mcg N=2136 (%) Upper Respiratory Tract Infection 123 (5.7) 102 (4.8) 115 (5.4) Pneumonia 98 (4.6) 61 (2.9) 107 (5.0) Back pain 67 (3.1) 55 (2.6) 64 (3.0) Oral candidiasis 65 (3.0) 24 (1.1) 57 (2.7) Influenza 63 (2.9) 42 (2.0) 61 (2.9) Muscle spasms 60 (2.8) 19 (0.9) 53 (2.5) Urinary tract...

    • Drug Interactions

    7 DRUG INTERACTIONS No formal drug interaction studies have been performed with BREZTRI AEROSPHERE.

  • Strong cytochrome P450 3A4 inhibitors (e.g. ritonavir): Use with caution. May cause systemic corticosteroid 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 , 7.4 )
  • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. ( 7.5 )
  • Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.6 )
  • Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of BREZTRI AEROSPHERE with other anticholinergic-containing drugs. ( 7.7 ) 7.1 Inhibitors of Cytochrome P450 3A4 The main route of metabolism of corticosteroids, including budesonide, a component of BREZTRI AEROSPHERE, is via cytochrome P450 isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of BREZTRI AEROSPHERE with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.9) ] . 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, a component of BREZTRI AEROSPHERE, 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 beta 2 -adrenergic agonists such as formoterol, a component of BREZTRI AEROSPHERE. 7.4 Non-Potassium Sparing Diuretics The hypokalemia and/or ECG changes that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta 2 -agonists, especially when the recommended dose of the beta 2 -agonist is exceeded. 7.5 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs BREZTRI AEROSPHERE, as with other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other 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 may be associated with...

    • Contraindications

    4 CONTRAINDICATIONS BREZTRI AEROSPHERE is contraindicated in patients who have demonstrated hypersensitivity to budesonide, glycopyrrolate, formoterol, or any of the excipients [see Warnings and Precautions (5.11) and Description (11) ] . Hypersensitivity to budesonide, glycopyrrolate, formoterol fumarate, or to any of the excipients. (4)

    Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with BREZTRI AEROSPHERE or with two of its individual components, glycopyrrolate or formoterol fumarate, in pregnant women to inform a drug-associated risk; however, studies are available for the other component, budesonide. In animal reproduction studies, budesonide alone, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at 0.3 and 0.75 times maximum recommended human daily inhaled dose (MRHDID), respectively, but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant women who received inhaled budesonide alone during pregnancy have not shown increased risk of abnormalities. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. Formoterol fumarate alone, administered by the oral route in rats and rabbits, caused structural abnormalities at 1500 and 61,000 times the MRHDID, respectively. Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No structural abnormalities, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 350 times the MRHDID. Glycopyrrolate alone, administered by the subcutaneous route in rats and rabbits, did not cause structural abnormalities or affect fetal survival at exposures approximately 2700 and 5400 times from MRHDID, respectively. Glycopyrrolate had no effects on the physical, functional, and behavioral development of rat pups with exposures up to 2700 times the MRHDID. The estimated background risk of major birth defects and miscarriage...

    Overdosage

    10 OVERDOSAGE No cases of overdose have been reported with BREZTRI AEROSPHERE. BREZTRI AEROSPHERE contains budesonide, glycopyrrolate, and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to BREZTRI AEROSPHERE. Treatment of overdosage consists of discontinuation of BREZTRI AEROSPHERE 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 medication can produce bronchospasm. Cardiac monitoring is recommended in case of overdosage. Budesonide If used at excessive doses for prolonged periods, systemic corticosteroid effects, such as hypercorticism may occur [see Warnings and Precautions (5.8) ] . Glycopyrrolate High doses of glycopyrrolate, a component of BREZTRI AEROSPHERE, 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. Formoterol Fumarate An overdose of formoterol fumarate would likely lead to an exaggeration of effects that are typical for beta 2 -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.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING BREZTRI AEROSPHERE Inhalation Aerosol:

  • 160 mcg budesonide, 9.0 mcg glycopyrrolate, and 4.8 mcg formoterol fumarate per inhalation
  • is supplied as a pressurized aluminum canister with an attached dose indicator, a yellow plastic actuator, a white mouthpiece, and a grey plastic dust cap.
  • contains 28 or 120 inhalations per canister: Pack size Net fill weight NDC 120-inhalation canister 10.7 grams 0310-4616-12 28-inhalation canister (institutional pack) 5.9 grams 0310-4616-39
  • each canister of BREZTRI AEROSPHERE is packaged in a foil laminate pouch with a desiccant sachet and is placed into a carton.
  • each carton contains one canister and Patient Information. The BREZTRI AEROSPHERE canister should only be used with the BREZTRI AEROSPHERE actuator, and the BREZTRI AEROSPHERE actuator should not be used with any other inhalation drug product. The correct amount of medication in each inhalation cannot be assured after the label number of inhalations from the canister have been used, when the dose indicator display window shows zero in the red zone, even though the canister may not feel completely empty. BREZTRI AEROSPHERE should be discarded when the dose indicator display window shows zero in the red zone or 3 months (for the 120-inhalation canister) or 3 weeks (for the 28-inhalation canister) after removal from the foil pouch, whichever comes first. Never immerse the canister into water to determine the amount remaining in the canister (“float test”). Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP]. Keep in a dry place away from heat and sunlight. For best results, the canister should be at room temperature before use. Shake well before using. Keep out of reach of children. CONTENTS UNDER PRESSURE Do not puncture. Do not use or store near heat or open flames. Exposure to temperatures above 120°F (49°C) may cause bursting. Never throw canister into...

    • About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.