budesonide inhaled/formoterol/glycopyrrolate inhaled (Rx)

1-10%

Upper respiratory tract infection (5.7%)

Pneumonia (4.6%)

Dysphonia (3.3%)

Muscle spasms (2.8-3.3%)

Back pain (3.1%)

Oral candidiasis (3%)

Influenza (2.9%)

Urinary tract infection (2.7%)

Cough (2.7%)

Sinusitis (2.6%)

Diarrhea (2.1%)

<1%

Cataracts

Frequency Not Defined

Other adverse effects associated ≥1 of the individual components

• Hyperglycemia
• Anxiety
• Insomnia
• Headache
• 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 dose

Pregnancy 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