glycopyrrolate inhaled/formoterol (Bevespi Aerosphere)

Dosing and uses of Bevespi Aerosphere (glycopyrrolate inhaled/formoterol)

• Adult
• Pediatric

 

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)