glycopyrrolate inhaled/formoterol (Bevespi Aerosphere)
Classes: Respiratory Inhalant Combos; Anticholinergics, Respiratory; Beta2 Agonists; COPD Agents
Dosing and uses of Bevespi Aerosphere (glycopyrrolate inhaled/formoterol)
Adult dosage forms and strengths
glycopyrrolate/formoterol fumarate
inhalation aerosoL
- (9mcg/4.8mcg)/inhalation
Chronic Obstructive Pulmonary Disease (COPD)
Combination inhalant containing long-acting muscarinic antagonist (LAMA) plus a long-acting beta2-agonist (LABA) indicated for the long-term, maintenance treatment of airflow obstruction with COPD, including chronic bronchitis and/or emphysema
2 inhalations (ie, 18 mcg/9.6 mcg) PO BID (morning and evening)
Do not exceed 2 inhalations BId
Dosage modifications
Renal impairment
- Studies not conducted
- Severe (CrCl ≤30 mL/min/1.73 m²) or end-stage renal disease requiring dialysis: Use only if expected benefit outweighs the potential risk
Hepatic impairment
- Studies not conducted
- Since formoterol fumarate is predominantly cleared by hepatic metabolism, impairment may lead to plasma formoterol accumulation; monitor closely
Dosing Considerations
Limitations of use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma
Pediatric dosage forms and strengths
Safety and efficacy not established
Bevespi Aerosphere (glycopyrrolate inhaled/formoterol) adverse (side) effects
1-10%
Cough (4%)
Urinary tract infection (2.6%)
Arthralgia (<2%)
Chest pain (<2%)
Tooth abscess (<2%)
Muscle spasms (<2%)
Headache (<2%)
Oropharyngeal pain (<2%)
Vomiting (<2%)
Pain in extremity (<2%)
Dizziness (<2%)
Anxiety (<2%)
Dry mouth (<2%)
Fall (<2%)
Influenza (<2%)
Fatigue (<2%)
Acute sinusitis (<2%)
Contusion (<2%)
Frequency not defined
FormoteroL
- Hypersensitivity reactions
- Hyperglycemia
- Sleep disturbance
- Agitation
- Restlessness
- Tremor
- Nausea
- Tachycardia
- Palpitations
- Cardiac arrhythmias
Warnings
Black box warnings
Long-acting beta2-adrenergic agonists (LABAs) increase the risk of asthma-related death
Data from a large placebo-controlled US study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeteroL
This finding with salmeterol is considered a class effect of all LABAs, including indacateroL
Safety and efficacy of indacaterol/glycopyrrolate in patients with asthma have not been established
Not indicated for the treatment of asthma
Contraindications
Hypersensitivity
All LABAs are contraindicated in patients with asthma without use of a long-term asthma control medication; not indicated for the treatment of asthma
Cautions
Data from a large placebo-controlled US study in asthma patients showed that LABAs may increase the risk of asthma-related death (see Black box warnings)
Should not be initiated in patients with acutely deteriorating or potentially life-threatening episodes of COPD; also do not use for the relief of acute symptoms (ie, as rescue therapy) for treating acute episodes of bronchospasm
Do not use more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result
Can produce paradoxical bronchospasm that may be life-threatening; treat immediately with an inhaled, short-acting bronchodilator, discontinue therapy, and institute alternative therapy
Immediate hypersensitivity reactions have been reported after administration of formoterol or glycopyrrolate
LABAs can produce clinically significant cardiovascular effects, including increases in pulse rate or systolic or diastolic blood pressure; if such effects occur, discontinue therapy
Caution with convulsive disorders, thyrotoxicosis, patients who are unusually responsive to sympathomimetic amines, narrow-angle glaucoma (may worsen), or urinary retention (eg, prostatic hyperplasia, bladder-neck obstruction); instruct patients to contact their physician immediately with worsening disease symptoms
Doses of the related beta2-agonist albuterol, when administered IV, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis owing to transient hyperglycemia; use caution
LABAs may produce significant hypokalemia, which has the potential to produce adverse cardiovascular effect; in patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility for cardiac arrhythmias; the decrease in serum potassium is usually transient, not requiring supplementation
Pregnancy and lactation
Pregnancy
There are no adequate and well-controlled studies in humans with Bevespi Aerosphere or its individual components
Single-dose studies in humans found that a very small amount of glycopyrrolate passed the placental barrier
Animal studies
- Glycopyrrolate
- There was no evidence of teratogenic effects in rats and rabbits at approximately 18,000 and 270 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults
- Formoterol fumarate
- Formoterol fumarate has been shown to be teratogenic, to be embryocidal, to increase pup loss at birth and during lactation, and to decrease pup weights in rats and teratogenic in rabbits
- These effects were observed at approximately 1,500 (rats) and 61,000 (rabbits) times the MRHDID
- Other observations in animal studies included umbilical hernia, prolonged pregnancy, fetal brachygnathia, and liver cysts
Lactation
Unknown if distributed in human breast milk
Since there are no data from controlled trials by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of drug treatment to the mother
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.
Pharmacology of Bevespi Aerosphere (glycopyrrolate inhaled/formoterol)
Mechanism of action
Glycopyrronium: Long-acting muscarinic antagonist (LAMA); often referred to as an anticholinergic; produces bronchodilation by inhibiting acetylcholine’s effect on muscarinic receptors in the airway smooth muscle
Formoterol: Long-acting beta2-agonist (LABA) with a rapid onset of action; stimulates intracellular adenyl cyclase, causing conversion of ATP to cyclic AMP; increased cyclic AMP levels cause relaxation of bronchial smooth muscle
Absorption
Peak plasma concentration: 5 min (glycopyrrolate); 20-60 min (formoterol)
Steady-state achieved: 2-3 days
Extent of systemic exposure increases at steady state compared to first dose; 2.3 x higher (glycopyrrolate) and 1.5 x higher (formoterol)
Distribution
Protein bound: 46-58% (formoterol)
Vd (central compartment): 951 L (glycopyrrolate); 948 L (formoterol)
Vd (peripheral compartment): 2019 L (glycopyrrolate); 434 L (formoterol)
Metabolism
Glycopyrrolate: metabolism plays a minor role in the overall elimination of glycopyrrolate
FormoteroL
- Primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites
- Secondary metabolic pathways include deformylation and sulfate conjugation
- CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation
Elimination
Half-life: 11.8 hr (glycopyrrolate); 11.8 hr (formoterol)
Elimination
- Glycopyrrolate: 85% urine; small amount in bile
- Formoterol: 62% in urine; 24% in feces
Administration
Orally Inhaled Administration
Shake well before each use
Do not exceed 2 inhalations twice daily
Canister contains 120 inhalations and has an attached dose indicator, which indicates how many inhalations remain
The dose indicator display will move after every tenth actuation
When nearing the end of the usable inhalations, the color behind the number in the dose indicator display window changes to red
Discarded when the dose indicator display window shows zero
Prime device
- Prime the inhaler to ensure appropriate drug content in each actuation
- Prime before using for the first time
- To prime, release 4 sprays into the air away from the face, shaking well before each spray
- Must be reprimed when the inhaler has not been used for >7 days; to reprime, release 2 sprays into the air away from the face; shake canister well before each spray
Storage
Store at controlled room temperature 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)