Introduction
This document may NOT be shared or otherwise distributed outside of AstraZeneca.
The Prescribing Information (PI) contains product information approved by the US Food and Drug Administration (FDA) based on the information collected by a manufacturer during preclinical research and clinical studies. For drugs that have been marketed, it also includes information from the postmarketing clinical experience.
The FDA considers the PI to be a part of product labeling, which is intended to provide clinicians with the manufacturer's guidelines for using the prescription product.
Learning Objectives
After completing this Annotated PI WBT, you should be able to:
Explain the contents of the boxed warning
State the approved indications for BEVESPI AEROSPHERE
Describe how BEVESPI AEROSPHERE is dosed and administered
Identify the available dosage forms and strengths for BEVESPI AEROSPHERE
Identify the contraindications to the use of BEVESPI AEROSPHERE
Describe the warnings and precautions for BEVESPI AEROSPHERE
State the adverse reactions and drug interactions that may be associated with BEVESPI AEROSPHERE
Describe the use of BEVESPI AEROSPHERE in specific populations
Discuss options in the event of overdosage with BEVESPI AEROSPHERE
Identify the active ingredients of BEVESPI AEROSPHERE
Describe the active ingredients of BEVESPI AEROSPHERE
Describe the mechanism of action of BEVESPI AEROSPHERE
Describe the pharmacokinetics and pharmacodynamics of BEVESPI AEROSPHERE
Describe the nonclinical toxicology of BEVESPI AEROSPHERE
Describe the overall design and methods of the clinical studies cited in the BEVESPI AEROSPHERE PI
Identify the key efficacy results of the clinical studies cited in the BEVESPI AEROSPHERE PI
Describe how BEVESPI AEROSPHERE is supplied, stored, and handled
Explain the Patient Counseling Information section in the PI
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BEVESPI AEROSPHERE safely and effectively. See full prescribing information for BEVESPI AEROSPHERE.
BEVESPI AEROSPHERE™ (glycopyrrolate and formoterol fumarate) inhalation aerosol, for oral inhalation use
Initial U.S. Approval: 2016
Do not initiate in acutely deteriorating COPD or to treat acute symptoms. (5.2)
Do not use in combination with an additional medicine containing a LABA because of risk of overdose. (5.3, 7.1)
If paradoxical bronchospasm occurs, discontinue BEVESPI AEROSPHERE and institute alternative therapy. (5.4)
Use with caution in patients with cardiovascular disorders. (5.6)
Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.7)
ORGANIZATION OF THE PI
The first page of the PI contains highlights from the full PI. The highlights section is simply a short summary and does not include all the information needed to use BEVESPI AEROSPHERE safely and effectively. The full PI should be referred to when using BEVESPI AEROSPHERE.
FOR YOUR CLARIFICATION
Topics under this section are limited to:
Boxed Warning
Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
FOR YOUR CLARIFICATION
The data in these sections are further detailed in the full PI, and therefore, a full descriptive analysis will be provided when discussing these sections under the full PI.
WARNING: ASTHMA-RELATED DEATH
See full prescribing information for complete boxed warning.
Long-acting beta2-adrenergic agonists (LABAs), such as formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including formoterol fumarate. (5.1)
The safety and efficacy of BEVESPI AEROSPHERE in patients with asthma have not been established. BEVESPI AEROSPHERE is not indicated for the treatment of asthma. (5.1)
INDICATIONS AND USAGE
BEVESPI AEROSPHERE is a combination of glycopyrrolate, an anticholinergic, and formoterol fumarate, a long-acting beta2-adrenergic agonist (LABA) indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). (1)
Limitation of Use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma. (1, 5.1, 5.2)
DOSAGE AND ADMINISTRATION
For oral inhalation only.
Maintenance treatment of COPD: 2 inhalations of BEVESPI AEROSPHERE twice daily. (2)
DOSAGE FORMS AND STRENGTHS
Inhalation aerosol: Pressurized metered dose inhaler containing a combination of glycopyrrolate (9 mcg) and formoterol fumarate (4.8 mcg) as an inhalation aerosol.
Two inhalations equal one dose. (3)
CONTRAINDICATIONS
All LABAs are contraindicated in patients with asthma without use of a long-term asthma controller medication. (4) BEVESPI AEROSPHERE is not indicated for the treatment of asthma. (1)
Hypersensitivity to glycopyrrolate, formoterol fumarate, or to any component of this product. (4, 5.5)
WARNINGS AND PRECAUTIONS
Be alert to hypokalemia and hyperglycemia. (5.8)
Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a physician immediately if symptoms occur. (5.9)
Worsening urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a physician immediately if symptoms occur. (5.10)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥2% and more common than with placebo) include: urinary tract infection and cough. (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.
DRUG INTERACTIONS
Other adrenergic drugs may potentiate effect: Use with caution (5.3, 7.1)
Xanthine derivatives, steroids, diuretics or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. (7.2, 7.3)
Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium sparing diuretics may worsen with concomitant beta2-agonists. (7.3)
Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. (7.4)
Beta-blockers: Use with caution and only when medically necessary. (7.5)
Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administrations of BEVESPI AEROSPHERE with other anticholinergic-containing drugs. (7.6)
USE IN SPECIFIC POPULATIONS
Use in patients with severe renal impairment should be considered if the potential benefit of the treatment outweighs the risk. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
Revised: 4/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ASTHMA-RELATED DEATH3
1INDICATIONS AND USAGE3
2DOSAGE AND ADMINISTRATION3
3DOSAGE FORMS AND STRENGTHS4
4CONTRAINDICATIONS4
5WARNINGS AND PRECAUTIONS4
5.1.Asthma-Related Death4
5.2.Deterioration of Disease and Acute Episodes4
5.3.Excessive Use of BEVESPI and Use with Other Long-
Acting Beta2-Agonists5
5.4.Paradoxical Bronchospasm5
5.5.Hypersensitivity Reactions5
5.6.Cardiovascular Effects6
5.7.Coexisting Conditions6
5.8.Hypokalemia and Hyperglycemia6
5.9.Worsening of Narrow-Angle Glaucoma6
5.10.Worsening of Urinary Retention6
6ADVERSE REACTIONS7
6.1.Clinical Trials Experience7
7DRUG INTERACTIONS8
7.1.Adrenergic Drugs8
7.2.Xanthine Derivatives, Steroids, or Diuretics9
7.3.Non-Potassium Sparing Diuretics9
7.4.Monoamine Oxidase Inhibitors, Tricyclic
Antidepressants, QTc Prolonging Drugs9
7.5.Beta-Blockers9
7.6.Anticholinergics9
8USE IN SPECIFIC POPULATIONS10
8.1.Pregnancy10
8.2.Labor and Delivery10
8.3.Nursing Mothers11
8.4.Pediatric Use11
8.5.Geriatric Use11
8.6.Hepatic Impairment11
8.7.Renal Impairment11
10OVERDOSAGE11
11DESCRIPTION12
12CLINICAL PHARMACOLOGY14
12.1.Mechanism of Action14
12.2.Pharmacodynamics15
12.3.Pharmacokinetics15
13NONCLINICAL TOXICOLOGY17
13.1.Carcinogenesis, Mutagenesis, Impairment of
Fertility17
14CLINICAL STUDIES18
14.1.Dose-Ranging Trials18
14.2.Confirmatory Trials20
16HOW SUPPLIED/STORAGE AND HANDLING23
17PATIENT COUNSELING INFORMATION24
*Sections or subsections omitted from the full prescribing information are not listed
FULL PRESCRIBING INFORMATION
WARNING: ASTHMA-RELATED DEATH
Long-acting beta2-adrenergic agonists (LABAs) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE.
The safety and efficacy of BEVESPI AEROSPHERE in patients with asthma have not been established. BEVESPI AEROSPHERE is not indicated for the treatment of asthma. [see Warnings and Precautions (5.1)]
ORGANIZATION OF THE PI
A boxed warning may appear as part of the PI to highlight certain contraindications or serious warnings, particularly those that may lead to death or serious injury.
In the BEVESPI AEROSPHERE PI, the boxed warning section contains a specific warning about an increased risk of asthma-related death associated with the use of long-acting beta2-adrenergic agonists (LABAs).
As you review this information, you should be aware that additional details regarding these warnings are also provided in the Warnings and Precautions section (section 5).
FOR YOUR CLARIFICATION
A large placebo-controlled US trial assessing the safety of salmeterol (another LABA) with placebo added to usual asthma therapy found a small but significant increase in respiratory deaths in patients with asthma prescribed salmeterol.
LABAs are used to treat both asthma and chronic obstructive pulmonary disease (COPD). However, the studies reviewed by the FDA only included patients using LABAs for the treatment of asthma. There is no evidence to conclude that people with COPD who use LABAs are at any greater risk compared with people with COPD who do not use LABAs. The FDA does not recommend any change in the use of LABAs for the treatment of COPD.
All products that contain a LABA approved in the United States carry a boxed warning regarding an increased risk of asthma-related death.
For additional details regarding the LABA drug class, please refer to the Clinical Rationale and Pharmacology of LAMA + LABA module or the LAMA + LABA Competitive Landscape module of the BEVESPI AEROSPHERE Learning Center.
1 INDICATIONS AND USAGE
BEVESPI AEROSPHERE is a combination of glycopyrrolate and formoterol fumarate indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Important Limitation of Use: BEVESPI AEROSPHERE is not indicated for the relief of acute bronchospasm or for the treatment of asthma. [see Warnings and Precautions (5.1, 5.2)].
FOR YOUR CLARIFICATION
The safety and efficacy of BEVESPI AEROSPHERE in patients with asthma have not been established. BEVESPI AEROSPHERE is not indicated for the treatment of asthma.
Acute symptoms should be treated with an inhaled short-acting beta2-agonist (SABA; section 5.2).
2 DOSAGE AND ADMINISTRATION
BEVESPI AEROSPHERE (glycopyrrolate/formoterol fumarate 9 mcg/4.8 mcg) should be administered as two inhalations taken twice daily in the morning and in the evening by the orally inhaled route only. Do not take more than two inhalations twice daily.
BEVESPI AEROSPHERE contains 120 inhalations per canister. The canister 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. BEVESPI AEROSPHERE should be discarded when the dose indicator display window shows zero.
KEY CONCEPT
BEVESPI AEROSPHERE should be administered as 2 inhalations taken twice daily (also referred to as BID administration) by the orally inhaled route only. Do not take more than 2 inhalations twice daily.
Images of BEVESPI AEROSPHERE Inhaler and Dose Indicator
Priming BEVESPI AEROSPHERE is essential to ensure appropriate drug content in each actuation. Prime BEVESPI AEROSPHERE before using for the first time. To prime BEVESPI AEROSPHERE, release 4 sprays into the air away from the face, shaking well before each spray. BEVESPI AEROSPHERE must be re-primed when the inhaler has not been used for more than 7 days. To re-prime BEVESPI AEROSPHERE, release 2 sprays into the air away from the face, shaking well before each spray.
3 DOSAGE FORMS AND STRENGTHS
Inhalation Aerosol: BEVESPI AEROSPHERE is a pressurized metered dose inhaler that delivers 9 mcg of glycopyrrolate and 4.8 mcg of formoterol fumarate per inhalation. Two inhalations equal one dose. BEVESPI AEROSPHERE contains 120 inhalations per canister. The canister has an attached dose indicator and is supplied with a white plastic actuator with an orange dust cap.
KEY CONCEPT
BEVESPI AEROSPHERE is a fixed-dose pressurized metered-dose inhaler (pMDI) with only 1 dosage form and 1 dosage strength per bronchodilator drug. When used as indicated, 120 inhalations corresponds to a 30-day supply of treatment.
4 CONTRAINDICATIONS
All LABAs are contraindicated in patients with asthma without use of a long-term asthma control medication [see Warnings and Precautions (5.1)]. BEVESPI AEROSPHERE is not indicated for the treatment of asthma.
BEVESPI AEROSPHERE is contraindicated in patients with hypersensitivity to glycopyrrolate, formoterol fumarate, or to any component of the product [see Warnings and Precautions (5.5)].
ORGANIZATION OF THE PI
Section 4 of the full PI is the Contraindications section. It describes any situations in which the drug should not be used because the risk of use clearly outweighs any possible therapeutic benefit.
KEY CONCEPT
LABAs should never be used alone as monotherapy in patients with asthma. Instead, they should be prescribed in combinations with a long-term asthma control medication. Remember that BEVESPI AEROSPHERE is not indicated for the treatment of asthma.
Please refer to the Boxed Warning or the Warnings and Precautions section of the PI for additional details.
FOR YOUR CLARIFICATION
Hypersensitivity can occur from an immune response to a drug and results in inflammation and organ dysfunction.
The components of BEVESPI AEROSPHERE include glycopyrrolate and formoterol fumarate drug crystals, porous particles comprised of the phospholipid, 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC), calcium chloride, and HFA 134a.
If a hypersensitivity reaction occurs, therapy with BEVESPI AEROSPHERE should be stopped at once and alternative treatment should be considered.
5 WARNINGS AND PRECAUTIONS
5.1. Asthma-Related Death
Data from a large placebo-controlled trial in subjects with asthma showed that LABAs may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by LABAs.
A 28-week, placebo-controlled US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of LABAs, including formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE.
No trial adequate to determine whether the rate of asthma-related deaths is increased in patients treated with BEVESPI AEROSPHERE has been conducted. The safety and efficacy of BEVESPI AEROSPHERE in patients with asthma have not been established. BEVESPI AEROSPHERE is not indicated for the treatment of asthma.
ORGANIZATION OF THE PI
Section 5 of the full PI is the Warnings and Precautions section. It describes clinically significant adverse reactions, potential safety hazards, limitations to use imposed by these adverse reactions and safety hazards, and steps that should be taken if these adverse reactions occur.
There are 10 subsections within the Warnings and Precautions section.
FOR YOUR CLARIFICATION
LABAs may increase the risk of asthma-related death. The increased risk of asthma-related death is considered a class effect of LABAs, including formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE.
It is important to note that:
Data are not available to determine whether the rate of death in patients with COPD is increased by LABAs
FOR YOUR CLARIFICATION
It is also important to note that:
The effect of BEVESPI AEROSPHERE on the rate of asthma-related deaths is unknown
The safety and efficacy of BEVESPI AEROSPHERE in patients with asthma have not been established
BEVESPI AEROSPHERE is not indicated for the treatment of asthma
5.2. Deterioration of Disease and Acute Episodes
BEVESPI AEROSPHERE should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. BEVESPI AEROSPHERE has not been studied in patients with acutely deteriorating COPD. The use of BEVESPI AEROSPHERE in this setting is inappropriate.
KEY CONCEPT
BEVESPI AEROSPHERE should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition.
BEVESPI AEROSPHERE should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BEVESPI AEROSPHERE has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.
When beginning BEVESPI AEROSPHERE, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these medicines and use them only for symptomatic relief of acute respiratory symptoms. When prescribing BEVESPI AEROSPHERE, the healthcare provider should also prescribe an inhaled, short acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.
KEY CONCEPT
BEVESPI AEROSPHERE should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm.
KEY CONCEPT
When prescribing BEVESPI AEROSPHERE, health care providers should:
Instruct patients who have been taking inhaled SABAs on a regular basis (eg, 4 times/day) to discontinue the regular use of these medicines and use them only for symptomatic relief of acute respiratory symptoms
KEY CONCEPT
When prescribing BEVESPI AEROSPHERE, health care providers should:
Prescribe an inhaled SABA and instruct the patient on how it should be used for symptomatic relief of acute respiratory symptoms
COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BEVESPI AEROSPHERE no longer controls the symptoms of bronchoconstriction, or the patient's inhaled, short-acting beta2-agonist becomes less effective, or the patient needs more inhalations of short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of BEVESPI AEROSPHERE beyond the recommended dose is not appropriate in this situation.
KEY CONCEPT
COPD may deteriorate acutely over a period of hours or chronically over several days or longer. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Markers of deterioration of disease may include:
BEVESPI AEROSPHERE no longer controls the symptoms of bronchoconstriction
The patient’s inhaled SABA becomes less effective
The patient needs more inhalations of SABA than usual
Increasing the daily dosage of BEVESPI AEROSPHERE beyond the recommended dose is not appropriate in this situation.
5.3. Excessive Use of BEVESPI and Use with Other Long-Acting Beta2-Agonists
As with other inhaled medicines containing beta2-agonists, BEVESPI AEROSPHERE should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic medicines. Patients using BEVESPI AEROSPHERE should not use another medicine containing a LABA for any reason [see Drug Interactions (7.1)].
FOR YOUR CLARIFICATION
To prevent the risk of overdose (as with other inhaled medicines containing beta2-agonists), BEVESPI AEROSPHERE should not be used:
More often than recommended
At higher doses than recommended
In conjunction with other medications containing LABAs
Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic medicines. Sympathomimetic medicines are drugs that produce effects resembling those resulting from stimulation of the sympathetic nervous system, which includes beta2-agonists.
5.4. Paradoxical Bronchospasm
As with other inhaled medicines, BEVESPI AEROSPHERE can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BEVESPI AEROSPHERE, it should be treated immediately with an inhaled, short-acting bronchodilator, BEVESPI AEROSPHERE should be discontinued immediately, and alternative therapy should be instituted.
FOR YOUR CLARIFICATION
Paradoxical bronchospasm refers to the contradictory constriction of the airways that may result from taking a sympathomimetic bronchodilator.
If paradoxical bronchospasm occurs following dosing with BEVESPI AEROSPHERE:
It should be treated immediately with an inhaled short-acting bronchodilator
BEVESPI AEROSPHERE should be discontinued immediately
Alternative therapy should be instituted
5.5. Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions have been reported after administration of glycopyrrolate or formoterol fumarate, the components of BEVESPI AEROSPHERE. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of tongue, lips and face), urticaria, or skin rash, BEVESPI AEROSPHERE should be stopped at once and alternative treatment should be considered.
KEY TERM
Immediate hypersensitivity reactions can occur from an immune response to a drug and result in inflammation and organ dysfunction.
5.6. Cardiovascular Effects
Formoterol fumarate, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms [see Clinical Pharmacology (12.2)]. If such effects occur, BEVESPI AEROSPHERE may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown.
Therefore, BEVESPI AEROSPHERE should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
FOR YOUR CLARIFICATION
Like other beta2-agonists, formoterol fumarate can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic (when the heart is contracting) or diastolic (when the heart is relaxing) blood pressure, or symptoms. If these effects occur, BEVESPI AEROSPHERE may need to be discontinued.
FOR YOUR CLARIFICATION
BEVESPI AEROSPHERE should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency (heart failure), cardiac arrhythmias (irregular heartbeat), and hypertension (high blood pressure).
5.7. Coexisting Conditions
BEVESPI AEROSPHERE, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
FOR YOUR CLARIFICATION
BEVESPI AEROSPHERE contains sympathomimetic amines, which are compounds that produce effects resembling those resulting from stimulation of the sympathetic nervous system. All medications containing sympathomimetic amines should be used with caution in patients:
With convulsive disorders (involuntary muscular contractions and relaxations)
With thyrotoxicosis (hyperthyroidism, or excessive quantities of thyroid hormones)
Who are unusually responsive to sympathomimetic amines
When administered intravenously, the related beta2-agonist albuterol has been reported to aggravate preexisting diabetes mellitus (metabolic disease resulting in elevated blood sugar levels) and ketoacidosis (excessive blood acidity caused by an accumulation of ketone bodies in advanced stages of uncontrolled diabetes mellitus).
5.8. Hypokalemia and Hyperglycemia
Beta2-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Beta2-agonist medicines may produce transient hyperglycemia in some patients. In two clinical trials of 24-weeks and a 28-week safety extension study evaluating BEVESPI AEROSPHERE in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.
FOR YOUR CLARIFICATION
Beta2-agonist medications may produce significant hypokalemia (low blood potassium) or transient hyperglycemia (high blood sugars) in some patients.
In 2 clinical trials of BEVESPI AEROSPHERE in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.
5.9. Worsening of Narrow-Angle Glaucoma
BEVESPI AEROSPHERE should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
FOR YOUR CLARIFICATION
BEVESPI AEROSPHERE should be used with caution in patients with narrow-angle glaucoma, a disease characterized by increased pressure within the eye.
Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma, which may include:
Eye pain or discomfort
Blurred vision
Visual halos or colored images associated with
Conjunctival congestion (fluid build-up within the mucous membrane that lines the eyelids)
Corneal edema (swelling of the cornea)
If any of these signs or symptoms develop, patients should immediately consult a physician.
5.10. Worsening of Urinary Retention
BEVESPI AEROSPHERE should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
FOR YOUR CLARIFICATION
Prescribers and patients should be alert for signs and symptoms of urinary retention (incomplete emptying of the bladder; eg, difficulty passing urine and painful urination), especially in patients with prostatic hyperplasia (enlargement of the prostate gland) or bladder-neck obstruction (condition where the bladder neck does not open enough during urination). If any of these signs or symptoms develop, patients should consult a physician immediately.
6 ADVERSE REACTIONS
ORGANIZATION OF THE PI
Section 6 of the full PI is the Adverse Reactions section. It describes the overall adverse reaction profile of the drug based on the entire safety database of the product. According to the FDA, this section only includes those adverse events for which there is some basis to believe there is a causal relationship between the adverse event and the drug.
LABAs, such as formoterol fumarate one of the active ingredients in BEVESPI AEROSPHERE, increase the risk of asthma-related death. BEVESPI AEROSPHERE is not indicated for the treatment of asthma [see Boxed Warning and Warnings and Precautions (5.1)].
The following adverse reactions are described in greater detail elsewhere in the labeling:
Paradoxical bronchospasm [See Warnings and Precautions (5.4)]
Hypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.5)]
Cardiovascular effects [See Warnings and Precautions (5.6)]
Worsening of narrow-angle glaucoma [See Warnings and Precautions (5.9)]
Worsening of urinary retention [See Warnings and Precautions (5.10)]
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 clinical program for BEVESPI AEROSPHERE included 4,911 subjects with COPD in two 24-week lung function trials, one long-term safety extension study of 28 weeks, and 10 other trials of shorter duration. A total of 1,302 subjects have received at least 1 dose of BEVESPI AEROSPHERE. The safety data described below are based on the two 24-week trials and the one 28-week long-term safety extension trial. Adverse reactions observed in the other trials were similar to those observed in these confirmatory trials.
FOR YOUR CLARIFICATION
This section begins with a disclaimer explaining that the adverse reactions observed in clinical trials for a particular drug cannot be compared to adverse reactions observed during the clinical trials of another drug. Additionally, the rates of adverse reactions of this drug in clinical trials may not be the same as what may occur in clinical practice.
FOR YOUR CLARIFICATION
The clinical program for BEVESPI AEROSPHERE included 4911 patients with COPD enrolled in:
2 lung function trials of 24-week duration each*
1 long-term (28 weeks) safety extension study*
10 other trials of shorter duration
*The safety data described in the Adverse Reactions section of the PI are based on these trials. Adverse reactions observed in the other trials were similar to those observed in these confirmatory trials.
To date, a total of 1302 patients have received at least 1 dose of BEVESPI AEROSPHERE.
24-Week TrialsThe incidence of adverse reactions with BEVESPI AEROSPHERE in Table 1 is based on reports in two 24-week, placebo-controlled trials (Trials 1 and 2; n=2,100 and n=1,610, respectively). Of the 3,710 subjects, 56% were male and 91% were Caucasian. They had a mean age of 63 years and an average smoking history of 51 pack-years, with 54% identified as current smokers. At screening, the mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV1) was 51% (range: 19% to 82%) and the mean percent reversibility was 20% (range: -32% to 135%).
Subjects received one of the following treatments: BEVESPI AEROSPHERE, glycopyrrolate 18 mcg, formoterol fumarate 9.6 mcg, or placebo twice daily or active control.
FOR YOUR CLARIFICATION
The demographics of the 3710 patients included in the two 24-week lung function trials (Trial 1: n=2100 and Trial 2: n=1610) were:
Male: 56%
Caucasian: 91%
Mean age: 63 years
Average smoking history: 51 pack-years (1 pack-year: approximately 365 packs of cigarettes annually)
Current smokers: 54%
Mean postbronchodilator percent predicted forced expiratory volume at 1 second (FEV1) at screening: 51% (range: 19% to 82%)
Mean percent reversibility: 20% (range: –32% to 135%)
FOR YOUR CLARIFICATION
Subjects received one of the following treatments:
BEVESPI AEROSPHERE
18 mcg glycopyrrolate alone
9.6 mcg formoterol fumarate alone
Placebo
Active control
Table 1 - Adverse Reactions with BEVESPI AEROSPHERE ≥2% Incidence and More Common than with Placebo in Subjects with Chronic Obstructive Pulmonary Disease
Adverse Reaction |
BEVESPI AEROSPHERE |
Glycopyrrolate 9 mcg |
Formoterol Fumarate 4.8 mcg |
Placebo |
---|---|---|---|---|
Respiratory, thoracic, and mediastinal disorders |
||||
Cough |
4.0 |
3.0 |
2.7 |
2.7 |
Infections and infestation |
||||
Urinary tract infection |
2.6 |
1.8 |
1.5 |
2.3 |
FOR YOUR CLARIFICATION
Table 1 demonstrates that cough and urinary tract infection were more common in the BEVESPI AEROSPHERE group compared with the placebo group. These results are based on Trials 1 and 2.
Other adverse reactions defined as events with an incidence of >1% but less than 2% with BEVESPI AEROSPHERE but more common than with placebo included the following: arthralgia, chest pain, tooth abscess, muscle spasms, headache, oropharyngeal pain, vomiting, pain in extremity, dizziness, anxiety, dry mouth, fall, influenza, fatigue, acute sinusitis, and contusion.
Long-Term Safety Extension Trial
In a 28-week long-term safety extension trial, 893 subjects who successfully completed Trial 1 or Trial 2 were treated for up to an additional 28 weeks for a total treatment period of up to 52 weeks with BEVESPI AEROSPHERE, glycopyrrolate 18 mcg, formoterol fumarate 9.6 mcg administered twice daily or active control. Because the subjects continued from Trial 1 or Trial 2 into the safety extension trial, the demographic and baseline characteristics of the long-term safety extension trial were similar to those of the placebo-controlled efficacy trials described above. The adverse reactions reported in the long-term safety trial were consistent with those observed in the 24-week placebo-controlled trials.
FOR YOUR CLARIFICATION
In a long-term safety extension trial, 893 patients who successfully completed Trial 1 or Trial 2 were treated for up to an additional 28 weeks, for a total treatment period of up to 52 weeks. The adverse reactions reported in the long-term safety trial were consistent with those observed in the 24-week placebo-controlled trials.
Additional Adverse Reactions: Other adverse reactions that have been associated with the component formoterol fumarate include: hypersensitivity reactions, hyperglycemia, sleep disturbance, agitation, restlessness, tremor, nausea, tachycardia, palpitations, cardiac arrhythmias (atrial fibrillation, supraventricular tachycardia, and extrasystoles).
7 DRUG INTERACTIONS
No formal drug interaction studies have been performed with BEVESPI AEROSPHERE.
ORGANIZATION OF THE PI
Section 7 of the full PI is the Drug Interactions section. It provides a description of clinically significant interactions, either observed or predicted, with other specific prescription or over-the-counter (OTC) drugs, classes of drugs, or foods. It also provides practical instructions for preventing or managing these interactions.
FOR YOUR CLARIFICATION
The Drug Interactions section of the BEVESPI AEROSPHERE PI does not contain any information on potential drug interactions because the appropriate drug interaction studies have not been performed.
7.1 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 BEVESPI AEROSPHERE, may be potentiated [see Warnings and Precautions (5.3)].
FOR YOUR CLARIFICATION
Patients taking adrenergic drugs should be mindful of the additional potential for sympathetic effects caused by the coadministration of BEVESPI AEROSPHERE, since it contains formoterol fumarate, a beta2-adrenergic agonist.
7.2. Xanthine Derivatives, Steroids, or Diuretics
Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of beta2 adrenergic agonists such as formoterol, a component of BEVESPI AEROSPHERE.
KEY TERMS
Xanthine derivatives are drugs used for the relief of bronchospasm caused by asthma or chronic obstructive lung disease. They inhibit tissue phosphodiesterases, resulting in increased cellular cyclic AMP. The most widely used xanthine is theophylline.
Steroids are drugs used to relieve inflammatory diseases (such as asthma or chronic obstructive lung disease; arthritis or colitis; or dermatitis or eczema) or as part of a treatment for some malignancies.
Diuretics (sometimes referred to as “water pills”) are agents that increase urine output. Diuretics are used to treat hypertension, congestive heart failure, and edema (swelling).
FOR YOUR CLARIFICATION
Xanthine derivatives, steroids, and diuretics may potentiate any hypokalemic (low blood potassium) effect of beta2 agonists.
7.3. Non-Potassium Sparing Diuretics
The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta2-agonists, especially when the recommended dose of the beta2-agonist is exceeded. Approximately 17% of subjects were taking non-potassium sparing diuretics during the two 24-week placebo-controlled trials in subjects with COPD. The incidence of adverse events in subjects taking non-potassium-sparing diuretics was similar between BEVESPI AEROSPHERE and placebo treatment groups. In addition, there was no evidence of a treatment effect on serum potassium with BEVESPI AEROSPHERE compared to placebo in subjects taking non-potassium sparing diuretics during the two 24-week trials. However, caution is advised in the coadministration of BEVESPI AEROSPHERE with non-potassium-sparing diuretics.
FOR YOUR CLARIFICATION
The electrocardiogram (ECG) changes (ie, changes in the electrical activity of the heart) and/or hypokalemia (low blood potassium) that may result from the administration of non–potassium-sparing diuretics can be acutely worsened by beta2-agonists, especially when the recommended dose of the beta2-agonist is exceeded.
KEY TERMS
A diuretic (sometimes referred to as a “water pill”) is an agent that increases urine output. Diuretics are used to treat hypertension, congestive heart failure, and edema (swelling).
Potassium-sparing diuretics stimulate the kidneys to excrete water and sodium while retaining potassium. Non–potassium-sparing diuretics do not retain potassium. Common side effects of non–potassium-sparing diuretics are potassium depletion, low blood pressure, dehydration, and hyponatremia (low blood sodium).
7.4. Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs
BEVESPI AEROSPHERE, as with other beta2-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 an increased risk of ventricular arrhythmias.
KEY TERMS
Monoamine oxidase inhibitors are a group of drugs that can be used to treat depression and Parkinson disease.
Tricyclic antidepressants are antidepressant agents whose chemical structure has 3 fused rings. These drugs block the cellular reuptake of certain neurotransmitters (norepinephrine and serotonin) at nerve endings.
KEY TERM
On an ECG, the QTc interval represents the interval between ventricular depolarization and repolarization adjusted for the patient’s heart rate. QTc prolongation refers to an increase in the duration of the QTc interval and is associated with an increased risk of disturbances of the ventricular rhythms and sudden death.
7.5. Beta-Blockers
Beta-adrenergic receptor antagonists (beta-blockers) and BEVESPI AEROSPHERE may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta2-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
KEY TERM
Beta-adrenergic receptor antagonists, also called beta-blockers, are any drugs that inhibit the activity of the sympathetic nervous system and of adrenergic hormones. Members of this class of drugs are used to treat cardiovascular diseases, glaucoma, and other conditions.
7.6. Anticholinergics
There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of BEVESPI AEROSPHERE with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.9, 5.10) and Adverse Reactions (6)].
KEY TERMS
Anticholinergic medications are drugs that block parasympathetic nerve impulses. One of the 2 active components of BEVESPI AEROSPHERE, glycopyrrolate, is an anticholinergic agent.
FOR YOUR CLARIFICATION
There is a potential for an additive interaction when different anticholinergic medications are used at the same time. Therefore, patients should avoid coadministration of BEVESPI AEROSPHERE with other anticholinergic-containing drugs, as this may lead to an increase in anticholinergic adverse effects (eg, dry mouth and blurred vision).
8 USE IN SPECIFIC POPULATIONS
8.1. Pregnancy
Teratogenic Effects:
Pregnancy Category C. There are no adequate and well-controlled trials of BEVESPI AEROSPHERE or its individual components, glycopyrrolate and formoterol fumarate, in pregnant women. Because animal reproduction studies are not always predictive of human response, BEVESPI AEROSPHERE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking BEVESPI AEROSPHERE.
ORGANIZATION OF THE PI
Section 8 of the full PI is the Use in Specific Populations section. It contains information about the use of the drug and potential risks in specific populations. It must include information for pregnancy, labor and delivery, nursing mothers, pediatric use, and geriatric use. Additional subsections may be included as needed.
KEY TERMS
Teratogenic effects are adverse effects on the normal cellular development in the embryo or fetus. Certain chemicals, some therapeutic and illicit drugs, radiation, and intrauterine viral infections are known to cause these effects.
The risk of usage of a pregnancy category C medication cannot be excluded but has not been proven. Individual considerations of risk and benefit guide drug usage in patients.
KEY CONCEPT
BEVESPI AEROSPHERE falls into pregnancy category C because there are no adequate and well-controlled studies of BEVESPI AEROSPHERE or its individual components (glycopyrrolate and formoterol fumarate) in pregnant women.
BEVESPI AEROSPHERE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking BEVESPI AEROSPHERE.
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 (on a mg/m2 basis at a maternal oral dose of 65 mg/kg/day in rats and at a maternal intramuscular injection dose of 0.5 mg/kg in rabbits).
Single-dose studies in humans found that very small amounts of glycopyrrolate passed the placental barrier.
Formoterol Fumarate: Formoterol fumarate has been shown to be teratogenic, 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 (on a mg/m2 basis at maternal oral doses of 3 mg/kg/day and above in rats and 60 mg/kg/day in rabbits). Umbilical hernia was observed in rat fetuses at approximately 1,500 times the MRHDID (on a mg/m2 basis at maternal oral doses of 3 mg/kg/day and above). Prolonged pregnancy and fetal brachygnathia was observed in rats at approximately 7600 times the MRHDID (on a mg/m2 basis at an oral maternal dose of 15 mg/kg/day in rats). In another study in rats, no teratogenic effects were seen at approximately 600 times the MRHDID (on a mg/m2 basis at maternal inhalation doses up to 1.2 mg/kg/day in rats).
Subcapsular cysts on the liver were observed in rabbit fetuses at an oral dose approximately 61,000 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 60 mg/kg/day in rabbits). No teratogenic effects were observed at approximately 3600 times the MRHDID (on a mg/m2 basis at maternal oral doses up to 3.5 mg/kg/day).
8.2. Labor and Delivery
There are no well-controlled human trials that have investigated the effects of BEVESPI AEROSPHERE on preterm labor or labor at term. Because beta2-agonists may potentially interfere with uterine contractility, BEVESPI AEROSPHERE should be used during labor only if the potential benefit justifies the potential risk.
FOR YOUR CLARIFICATION
BEVESPI AEROSPHERE should be used during labor only if the potential benefit justifies the potential risk.
8.3. Nursing Mothers
It is not known whether BEVESPI AEROSPHERE is excreted in human milk. Because many drugs are excreted in human milk and because formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE, has been detected in the milk of lactating rats, caution should be exercised when BEVESPI AEROSPHERE is administered to a nursing woman. Since there are no data from controlled trials on the use of BEVESPI AEROSPHERE by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue BEVESPI AEROSPHERE, taking into account the importance of BEVESPI AEROSPHERE to the mother.
FOR YOUR CLARIFICATION
It is not known whether BEVESPI AEROSPHERE is excreted in human milk. Caution should be exercised when BEVESPI AEROSPHERE is administered to a nursing woman.
8.4. Pediatric Use
BEVESPI AEROSPHERE is not indicated for use in children. The safety and effectiveness of BEVESPI AEROSPHERE in the pediatric population have not been established.
8.5. Geriatric Use
Based on available data, no adjustment of the dosage of BEVESPI AEROSPHERE in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.
The confirmatory trials of BEVESPI AEROSPHERE for COPD included 1,680 subjects aged 65 and older and, of those, 290 subjects were aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
8.6. Hepatic Impairment
Formal pharmacokinetic studies using BEVESPI AEROSPHERE have not been conducted in patients with hepatic impairment. However, since formoterol fumarate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of formoterol fumarate in plasma. Therefore, patients with hepatic disease should be closely monitored.
FOR YOUR CLARIFICATION
Patients with hepatic (liver) disease should be closely monitored.
8.7. Renal Impairment
Formal pharmacokinetic studies using BEVESPI AEROSPHERE have not been conducted in patients with renal impairment. In patients with severe renal impairment (creatinine clearance of ≤30 mL/min/1.73 m2) or end-stage renal disease requiring dialysis, BEVESPI AEROSPHERE should be used if the expected benefit outweighs the potential risk [see Clinical Pharmacology (12.3)].
FOR YOUR CLARIFICATION
BEVESPI AEROSPHERE should only be used in patients with severe renal (kidney) impairment (creatinine clearance of ≤30 mL/min/1.73 m2) or end-stage renal disease requiring dialysis, if the expected benefit outweighs the potential risk.
Creatinine clearance rate is a laboratory parameter for estimating the filtration rate of the kidney. The normal creatinine clearance rate is about 125 mL/min. Lower rates reflect renal insufficiency and possibly impaired excretion of many drugs and toxins from the body.
10 OVERDOSAGE
ORGANIZATION OF THE PI
Section 10 of the full PI is the Overdosage section. It contains information about the following, based on human and animal data:
Signs and symptoms and laboratory findings likely to be associated with overdosage
Potential complications of overdosage
Recommended general treatment procedures and specific measures for support of vital functions in case of an overdose
Concentrations of the drug associated with toxicity or death in animals
The amount of drug in a single dose that is ordinarily associated with symptoms of overdosage and the amount of the drug in a single dose that is likely to be life threatening in animals
No cases of overdose have been reported with BEVESPI AEROSPHERE.
No cases of overdose have been reported with BEVESPI AEROSPHERE. BEVESPI AEROSPHERE contains both glycopyrrolate and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to BEVESPI AEROSPHERE. Treatment of overdosage consists of discontinuation of BEVESPI 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.
Glycopyrrolate
High doses of glycopyrrolate, a component of BEVESPI 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. However, there were no systemic anticholinergic adverse effects following single inhaled doses up to 144 mcg in subjects with COPD.
Formoterol Fumarate
An overdose of formoterol fumarate would likely lead to an exaggeration of effects that are typical for beta2-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 abuse of formoterol fumarate.
FOR YOUR CLARIFICATION
High doses of glycopyrrolate 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 (severe obstruction to the normal flow of feces through the bowels)/difficulties in voiding
Treatment of overdosage consists of discontinuing BEVESPI AEROSPHERE together with instituting appropriate symptomatic and/or supportive therapy.
FOR YOUR CLARIFICATION
An overdose of formoterol fumarate would likely lead to an exaggeration of effects that are typical for beta2-agonists:
Cardiac arrest/death
Seizures (convulsions or other clinically detectable events caused by a sudden discharge of electrical activity in the brain)
Angina (a pain or pressure in the chest caused by inadequate blood flow and oxygenation of the heart muscle)
Hypertension/hypotension (high/low blood pressure), tachycardia (rapid heart rate)
Atrial and ventricular tachyarrhythmias (rapid irregular heartbeat)
Nervousness
Headache
Tremor
Palpitations (sensation of rapid or irregular beating of the heart)
Muscle cramps
Nausea/dizziness
Sleep disturbances
Metabolic acidosis (elevated acidity of the blood)
Hyperglycemia (high blood sugar)
Hypokalemia (low blood potassium)
Treatment of overdosage consists of discontinuing BEVESPI AEROSPHERE together with instituting appropriate symptomatic and/or supportive therapy.
11 DESCRIPTION
BEVESPI AEROSPHERE (glycopyrrolate and formoterol fumarate) Inhalation Aerosol is a pressurized metered-dose inhaler that contains a combination of micronized glycopyrrolate, an anticholinergic, and micronized formoterol fumarate, a long-acting beta2-adrenergic agonist, for oral inhalation.
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 C19H28BrNO3·, and the molecular weight is 398.33 g/mol. The structural formula is as follows:
ORGANIZATION OF THE PI
Section 11 of the full PI is the Description section. It contains both the proprietary and the established names of the drug; dosage form and administration route; and the class, chemical name and structural formula of the drug. It also includes qualitative and quantitative ingredient information, as well as other information.
KEY CONCEPT
BEVESPI AEROSPHERE is a pMDI that contains a combination of micronized (pulverized to reduce particle size) glycopyrrolate, an anticholinergic, and micronized formoterol fumarate, a long-acting beta2-adrenergic agonist, for oral inhalation.
FOR YOUR CLARIFICATION
The molecular structures of glycopyrrolate and formoterol fumarate, as well as their full chemical names, formulas, and properties, are provided in this section of the PI.
Glycopyrrolate contains two chiral centers (denoted by * in structure above) 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 (C19H24N2O4)2.C4H4O4.2H2O and the molecular weight is 840.91 g/mol. The structural formula is as follows:
Formoterol fumarate contains two chiral centers (denoted by * in structure above), and consists of a single enantiomeric pair (a racemate of R,R and S,S).
BEVESPI AEROSPHERE is formulated as a hydrofluoroalkane (HFA 134a) propelled pressurized metered dose inhaler containing 120 inhalations. The canister has an attached dose indicator and is supplied with a white plastic actuator body and mouthpiece with an orange dust cap.
After priming each actuation of the inhaler meters 10.4 mcg of glycopyrrolate (equivalent to 8.3 mcg of glycopyrronium) and 5.5 mcg of formoterol fumarate from the valve which delivers 9 mcg of glycopyrrolate (equivalent to 7.2 mcg of glycopyrronium) and 4.8 mcg of formoterol fumarate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. BEVESPI AEROSPHERE also contains porous particles that form a cosuspension with the drug crystals. The porous particles are comprised of the phospholipid, 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), and calcium chloride. Porous particles and HFA 134a are excipients in the formulation.
KEY TERM
A propellant is any agent that forces another to move in a desired direction. Inhaled medications rely on propellants to improve drug delivery to the lungs of patients. HFA propellants are used in metered-dose inhalers and can deliver drugs such as beta2-agonists or anticholinergic agents to the lungs of patients with asthma or COPD.
KEY CONCEPT
As described in Section 2 of the PI, the patient must release 4 sprays into the air away from his or her face, shaking well before each spray, to prime BEVESPI AEROSPHERE.
After priming, each spray of the inhaler meters 10.4 mcg of glycopyrrolate and 5.5 mcg of formoterol fumarate from the valve. This translates into a delivery of 9 mcg of glycopyrrolate and 4.8 mcg of formoterol fumarate from the actuator, which corresponds to the indicated dosage.
The actual amount of drug delivered to the lungs may depend on patient factors, such as their coordination between pressing the actuator (spray) button and breathing in through the delivery system.
BEVESPI AEROSPHERE also contains porous particles that form a cosuspension with the drug crystals. The porous particles comprise the phospholipid DSPC and calcium chloride. Porous particles and HFA-134a are considered to be the excipients (drug delivery vehicles) in the formulation.
Priming BEVESPI AEROSPHERE is essential to ensure appropriate drug content in each actuation. Prime BEVESPI AEROSPHERE before using for the first time. To prime BEVESPI AEROSPHERE, release 4 sprays into the air away from the face, shaking well before each spray.
If the product is not used for more than 7 days re-prime the device. To re-prime BEVESPI AEROSPHERE, release 2 sprays into the air away from the face, shaking well before each spray.
12 CLINICAL PHARMACOLOGY
ORGANIZATION OF THE PI
Section 12 of the full PI is the Clinical Pharmacology section. It contains information about the mechanism of action, pharmacodynamics, and pharmacokinetics of the drug.
12.1. Mechanism of Action
BEVESPI AEROSPHERE
BEVESPI AEROSPHERE contains both glycopyrrolate and formoterol fumarate. The mechanism of action described below for the individual components apply to BEVESPI AEROSPHERE. These drugs represent two different classes of medications (a long-acting muscarinic antagonist and a long-acting selective beta2-adrenoceptor agonist) that have different effects on clinical and physiological indices.
MECHANISM OF ACTION ANIMATION
Click play to view an animation of the mechanism of action of BEVESPI AEROSPHERE.
The mechanism of action of BEVESPI AEROSPHERE is briefly summarized in this animation. For additional details regarding the mechanism of action of the long-acting muscarinic antagonists (LAMAs) or LABAs, please refer to the Clinical Rationale and Pharmacology for LAMA + LABA module or the BEVESPI AEROSPHERE Mechanism of Action module of the BEVESPI AEROSPHERE Learning Center.
Glycopyrrolate
Glycopyrrolate is a long-acting antimuscarinic agent which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methylcholine and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted more than 12 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect.
KEY CONCEPT
A competitive antagonist is a drug that has to compete with the body’s natural chemicals to occupy the same receptor. In this case, glycopyrrolate competes with acetylcholine to bind to muscarinic receptors.
DEFINITION
Methylcholine and acetylcholine are chemical stimulants that can be used clinically to mimic the type of bronchoconstriction experienced by patients with asthma and COPD. They are useful for conducting airway challenge tests.
Formoterol Fumarate
Formoterol fumarate is a long-acting selective beta2-adrenergic agonist (beta2-agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. The in vitro binding selectivity to beta2- over beta1-adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta2-selectivity ratio than formoterol.
FOR YOUR CLARIFICATION
Formoterol fumarate is selective for beta2-adrenergic receptors. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors (predominant adrenergic receptors in bronchial smooth muscle) than at beta1-receptors (predominant adrenergic receptors in the heart).
Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.
The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol fumarate, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
In vitro tests show that formoterol fumarate is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol fumarate also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.
12.2. Pharmacodynamics
Cardiovascular effects: Healthy Subjects
The potential for QTc interval prolongation was assessed in a double-blind, single-dose, placebo- and positive-controlled crossover trial in 69 healthy subjects. The largest mean (90% upper confidence bound) differences from placebo in baseline-corrected QTcI for 2 inhalations of BEVESPI AEROSPHERE and glycopyrrolate/formoterol fumarate 72/19.2 mcg, were 3.1 (4.7) ms and 7.6 (9.2) ms, respectively, and excluded the clinically relevant threshold of 10 ms.
KEY TERM
QTc prolongation refers to an increase in the duration of the QTc interval on an ECG and is associated with an increased risk of disturbances of the ventricular rhythms and sudden death.
A dose-dependent increase in heart rate was also observed. The largest mean (90% upper confidence bound) differences from placebo in baseline-corrected heart rate were 3.3 (4.9) beats/min and 7.6 (9.5) beats/min seen within 10 minutes of dosing with 2 inhalations of BEVESPI AEROSPHERE and glycopyrrolate/formoterol fumarate 72/19.2 mcg, respectively.
Chronic Obstructive Pulmonary Disease
The effect of glycopyrrolate/formoterol fumarate on cardiac rhythm in subjects with COPD was assessed using 24-hour Holter monitoring in 2-week and 24-week trials. All treatments were administered as two inhalations twice daily. In the 2-week trial, the Holter monitoring population included 58 subjects on glycopyrrolate/formoterol fumarate 18/4.8 mcg, 58 subjects on glycopyrrolate 18 mcg, and 60 subjects on formoterol fumarate 4.8 mcg. In the 24-week trial, the Holter monitoring population included 171 subjects on BEVESPI AEROSPHERE, 160 subjects on glycopyrrolate 9 mcg, 174 subjects on formoterol fumarate 4.8 mcg, and 80 subjects on placebo. No clinically meaningful effects on cardiac rhythm were observed.
DEFINITION
A Holter monitor is a portable device small enough to be worn by a patient during normal activity and capable of storing up to 24 hours of the individual's ECG record.
KEY CONCEPT
No clinically meaningful effects on cardiac rhythm were observed during 24-hour Holter monitoring assessments in 2-week and 24-week trials.
12.3. Pharmacokinetics
Linear pharmacokinetics were observed for glycopyrrolate (dose range: 18 to 144 mcg) and formoterol fumarate (dose range: 2.4 to 19.2 mcg) after oral inhalation.
FOR YOUR CLARIFICATION
Pharmacokinetics is the study of drug absorption, distribution, metabolism, and excretion.
The pharmacokinetic properties of BEVESPI AEROSPHERE were studied over a dose range of 18 to 144 mcg for glycopyrrolate and 2.4 to 19.2 mcg for formoterol fumarate after oral inhalation.
Absorption
Glycopyrrolate: Following inhaled administration of BEVESPI AEROSPHERE in subjects with COPD, Cmax occurred at 5 minutes. Steady state is expected to be achieved within 2-3 days of repeated dosing of BEVESPI AEROSPHERE and the extent of exposure is approximately 2.3 times higher than after the first dose.
Formoterol Fumarate: Following inhaled administration of BEVESPI AEROSPHERE in subjects with COPD, Cmax occurred within 20 to 60 minutes. Steady state is expected to be achieved within 2-3 days of repeated dosing with BEVESPI AEROSPHERE and the extent of exposure is approximately 1.5 times higher than after the first dose.
KEY CONCEPT
The maximum drug concentration in the peripheral blood (Cmax) was reached at 5 minutes for glycopyrrolate and within 20 to 60 minutes for formoterol fumarate.
Steady state (the point at which the amount of a drug that is excreted is equal to the amount that is administered) is expected to be achieved within 2 to 3 days of repeated dosing for both glycopyrrolate and formoterol fumarate.
Distribution
Glycopyrrolate: Population pharmacokinetic analysis showed that estimated Vc/F (volume of the central compartment), and V2/F (volume of the peripheral compartment) are 951 L, and 2019 L, respectively.
DEFINITION
Following absorption, drugs become distributed throughout body fluids. This process is dependent on a number of physiologic factors and the particular properties of the drug.
Formoterol Fumarate: Population pharmacokinetic analysis showed that estimated Vc/F (volume of the central compartment), and V2/F (volume of the peripheral compartment) are 948 L, and 434 L, respectively. Over the concentration range of 10-500 nmol/L, plasma protein binding of formoterol ranged from 46% to 58%.
Metabolism
Glycopyrrolate: Based on information from the published literature, metabolism plays a minor role in the overall elimination of glycopyrrolate.
Formoterol Fumarate: The 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.
KEY CONCEPT
Metabolism plays a minor role in the overall elimination of glycopyrrolate. On the other hand, formoterol fumarate undergoes various chemical changes resulting in the production of inactive metabolites before being eliminated.
Elimination
Glycopyrrolate: After IV administration of a 0.2 mg radiolabeled glycopyrrolate, 85% of dose recovered was recovered in urine 48 hours post dose and some of radioactivity was also recovered in bile. The terminal elimination half-life derived via population pharmacokinetics analysis was 11.8 hours.
Formoterol Fumarate: The excretion of formoterol was studied in four healthy subjects following simultaneous administration of radiolabeled formoterol via the oral and IV routes. In that study, 62% of the radiolabeled formoterol was excreted in the urine while 24% was eliminated in the feces. The terminal elimination half-life derived via population pharmacokinetics analysis was 11.8 hours.
KEY CONCEPT
The terminal elimination half-life for both glycopyrrolate and formoterol fumarate was determined to be 11.8 hours.
Special Populations
Effect of age, sex, race/ethnicity, or body weight:
Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age, sex, race/ethnicity, or body weight on the pharmacokinetics of glycopyrrolate and formoterol.
Hepatic Impairment: Dedicated studies evaluating effect of hepatic impairment on the pharmacokinetics of glycopyrrolate and formoterol were not conducted.
Renal Impairment: Dedicated studies evaluating effect of renal impairment on the pharmacokinetics of glycopyrrolate and formoterol were not conducted. When glycopyrrolate was administered IV in uremic patients undergoing renal transplantation, mean elimination half-life was significantly longer (46.8 minutes) than in healthy patients (18.6 minutes). The mean AUC (10.6 hr-µg/L), mean plasma clearance (0.43 L/hr/kg), and mean 3-hour urine excretion (0.7%) for glycopyrrolate were also significantly different than those of controls (3.73 hr-µg/L, 1.14 L/hr/kg, and 50%, respectively). A population pharmacokinetic analysis using BEVESPI AEROSPHERE showed that formoterol systemic exposure (AUC0-12) in subjects with COPD with moderate renal impairment (45 mL/min creatinine clearance) is expected to be approximately 45% higher compared to subjects with COPD with normal renal function (94 mL/min creatinine clearance).
Drug Interactions
No pharmacokinetic interaction is expected when glycopyrrolate and formoterol fumarate are administered in combination by the inhaled route. Specific drug-drug interaction studies have not been performed with glycopyrrolate or formoterol fumarate.
13 NONCLINICAL TOXICOLOGY
13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
ORGANIZATION OF THE PI
Section 13 of the full PI is the Nonclinical Toxicology section. This section includes any results regarding carcinogenesis, mutagenesis, and impairment of fertility in animals with administration of the drug. Any significant animal data necessary for safe and effective use of the drug in humans that are not incorporated into other sections of the labeling must be included here.
FOR YOUR CLARIFICATION
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of BEVESPI AEROSPHERE. Since BEVESPI AEROSPHERE is a combination of glycopyrrolate and formoterol fumarate, this section describes the evidence of carcinogenesis, mutagenesis, and impairment of fertility for each drug individually.
Please note that this section uses the acronym MRHDID, which stands for Maximum Recommended Human Daily Inhalation Dose.
BEVESPI AEROSPHERE: Long-term studies in animals have not been performed to evaluate the carcinogenic potential of BEVESPI AEROSPHERE which contains glycopyrrolate and formoterol fumarate. The data described below for the individual components apply to BEVESPI AEROSPHERE.
Glycopyrrolate
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of inhaled glycopyrrolate or any other formulations of glycopyrrolate.
Glycopyrrolate was not mutagenic in the bacterial reverse mutation assay, the in vitro mammalian cell micronucleus assay in TK6 cells or the in vivo micronucleus assay in rats.
In reproduction studies in rats, dietary administration of glycopyrrolate resulted in diminished rates of conception in a dose-related manner. Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate.
Formoterol Fumarate
Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of formoterol fumarate.
In a 24-month carcinogenicity study in CD-1 mice, formoterol fumarate at oral doses of 0.1 mg/kg and above [approximately 25 times the maximum recommended human daily inhalation dose (MRHDID) on a mg/m2 basis] caused a dose-related increase in the incidence of uterine leiomyomas.
In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 130 mcg/kg (approximately 65 times the MRHDID on a mcg/m2 basis). No tumors were seen at 22 mcg/kg (approximately 10 times the MRHDID on a mcg/m2 basis).
Other beta-agonist drugs have similarly demonstrated increases in leiomyomas of the genital tract in female rodents. The relevance of these findings to human use is unknown.
Formoterol fumarate was not mutagenic or clastogenic in Ames Salmonella/microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, and rat micronucleus test.
A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15 mg/kg (approximately 7600 times the MRHDID on a mg/m2 basis). In a separate study with male rats treated with an oral dose of 15 mg/kg (approximately 7600 times the MRHDID on a mg/m2 basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No such effect was seen at 3 mg/kg (approximately 1500 times the MRHDID on a mg/m2 basis). No effect on fertility was detected in female rats at doses up to 15 mg/kg (approximately 7600 times the MRHDID on a mg/m2 basis).
14 CLINICAL STUDIES
The safety and efficacy of BEVESPI AEROSPHERE was evaluated in a clinical development program that included 8 dose-ranging trials and two placebo-controlled lung function trials of 24-weeks duration that included a 28-week extension study to evaluate safety over 1 year. The efficacy of BEVESPI AEROSPHERE is based on the dose ranging trials in 822 subjects with COPD and the 2 placebo-controlled confirmatory trials in 3,705 subjects with COPD.
ORGANIZATION OF THE PI
Section 14 of the full PI is the Clinical Studies section. According to the FDA, this section discusses the clinical studies that facilitate an understanding of how to the use drug safely and effectively.
KEY CONCEPT
The safety and efficacy of BEVESPI AEROSPHERE were evaluated in a clinical development program that included:
8 dose-ranging trials
2 placebo-controlled lung function trials of 24 weeks duration each
1 extension study of 28 weeks to evaluate safety after 1 year
The efficacy of BEVESPI AEROSPHERE is based on the:
8 dose-ranging trials (N=822)
2 placebo-controlled confirmatory trials (N=3705)
14.1. Dose-Ranging Trials
Dose selection for BEVESPI AEROSPHERE for COPD was primarily based on data for the individual components, glycopyrrolate and formoterol fumarate, in COPD patients. Based on the findings from these studies, glycopyrrolate/formoterol fumarate 18/9.6 mcg administered twice-daily was evaluated in the confirmatory COPD trials.
KEY CONCEPT
The selection of the approved dosage and administration for BEVESPI AEROSPHERE in patients with COPD was based on the findings of several dose-ranging trials. These trials compared the efficacy of various doses of the individual components (glycopyrrolate and formoterol fumarate) to select the doses to be used in the confirmatory trials.
Glycopyrrolate
Dose selection for glycopyrrolate was supported by a 14-day, randomized, double-blind, placebo-controlled, incomplete-block crossover trial evaluating 6 doses of glycopyrrolate (GP MDI 18 to 0.6 mcg) administered twice daily and an open-label active control in 140 subjects with COPD. A dose ordering was observed, with the glycopyrrolate 18 mcg demonstrating larger improvements in FEV1 over 12 hours compared with glycopyrrolate 9, 4.6, 2.4, 1.2, and 0.6 mcg (Figure 1).
Figure 1 - Mean Change from Baseline in FEV1 over Time on Day 14 (MITT Population)
The difference from placebo in change from baseline in trough FEV1 after 14 days for the 18, 9, 4.6, 2.4, 1.2, and 0.6 mcg doses were 97 mL (95% CI: 45, 149), 88 mL (95% CI: 37, 139), 75 mL (95% CI: 24, 125), 84 mL (95% CI: 33, 135), 76 mL (95% CI: 22, 129), and 37 mL (95% CI: -17, 91), respectively. Two additional dose ranging trials (single-dose and 7-day trials) in subjects with COPD demonstrated minimal additional benefit at doses above 18 mcg of glycopyrrolate. The results supported the selection of 18 mcg of glycopyrrolate twice daily in the confirmatory COPD trials.
Evaluations of the appropriate dosing interval for glycopyrrolate were conducted by comparing to a known drug dosed four times daily (open-label ipratropium bromide inhalation aerosol). The results supported the selection of a twice-daily dosing interval for further evaluation in the confirmatory COPD trials.
Formoterol Fumarate
Dose selection for formoterol fumarate was supported by a single-dose, randomized, double-blind, placebo-controlled, crossover trial evaluating 3 doses of formoterol fumarate (FF MDI 9.6, 4.8 and 2.4 mcg), an open-label active control, and placebo in 34 subjects with COPD. A dose ordering was observed with the formoterol fumarate 9.6 mcg dose demonstrating larger improvements in FEV1 over 12 hours compared with the lower doses of 4.8 and 2.4 mcg (Figure 2).
Figure 2 - Mean Change from Baseline in FEV1 over Time on Day 1
The differences in mean change from baseline in normalized FEV1 AUC0-12 for formoterol fumarate 9.6, 4.8, and 2.4 mcg compared to placebo were 176 mL (95% CI: 138, 214), 103 (95% CI: 66, 140), and 81 (95% CI: 45, 118), respectively. These results provided support for the selection of 9.6 mcg of formoterol fumarate twice daily in the confirmatory COPD trials.
14.2. Confirmatory Trials
The clinical development program for BEVESPI AEROSPHERE included two (Trial 1 and Trial 2) 24-week, randomized, double-blind, placebo-controlled, parallel-group trials in subjects with moderate to very severe COPD designed to evaluate the efficacy of BEVESPI AEROSPHERE on lung function. The 24-week trials included 3,699 subjects that had a clinical diagnosis of COPD, were between 40 and 80 years of age, had a history of smoking greater than or equal to 10 pack-years, had a post-albuterol FEV1 less than 80% of predicted normal values, and had a ratio of FEV1/FVC of less than 0.7. The majority of patients were male (56%) and Caucasian (91%) with a mean age of 63 years and an average smoking history of 51 pack-years (54% current smokers). During screening, mean post-bronchodilator percent predicted FEV1 was 51% (range: 19% to 82%) and mean percent reversibility was 20% (range: -32% to 135%).
KEY CONCEPT
The clinical development program for BEVESPI AEROSPHERE included 2 randomized, double-blind, placebo-controlled, parallel-group, 24-week trials in patients with moderate to very severe COPD. The trials are referred to in the PI as Trial 1 and Trial 2, and were designed to evaluate the efficacy of BEVESPI AEROSPHERE with regard to lung function.
These trials will only briefly be reviewed here. For additional information on the specifics of Trial 1 and Trial 2, please refer to the BEVESPI AEROSPHERE Clinical Trials Backgrounders (PINNACLE-1 and PINNACLE-2) of the BEVESPI AEROSPHERE Learning Center.
Trial 1 and Trial 2 evaluated BEVESPI AEROSPHERE (glycopyrrolate/formoterol fumarate) 18 mcg/9.6 mcg, glycopyrrolate 18 mcg, formoterol fumarate 9.6 mcg, and placebo administered twice daily (BID). Trial 1 also included an open-label active control.
The primary endpoint was change from baseline in trough FEV1 at Week 24 compared with placebo, glycopyrrolate 18 mcg BID, and formoterol fumarate 9.6 mcg BID. The comparison of BEVESPI AEROSPHERE with glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg was assessed to evaluate the contribution of the individual components to BEVESPI AEROSPHERE. In both trials, BEVESPI AEROSPHERE demonstrated a larger increase in mean change from baseline in trough FEV1 at Week 24 relative to placebo, glycopyrrolate 18 mcg, and formoterol fumarate 9.6 mcg (Table 2).
KEY CONCEPT
Patients in Trials 1 and 2 received 1 of the following treatments, administered twice daily:
BEVESPI AEROSPHERE (glycopyrrolate
18 mcg/formoterol fumarate 9.6 mcg)Glycopyrrolate 18 mcg
Formoterol fumarate 9.6 mcg
Placebo
The placebo, glycopyrrolate, and formoterol fumarate comparators used the same inhaler and excipients as BEVESPI AEROSPHERE.
KEY CONCEPT
The primary end point for BEVESPI AEROSPHERE was change from baseline in trough (predose) FEV1 at week 24 compared with placebo, glycopyrrolate 18 mcg BID alone, and formoterol fumarate 9.6 mcg BID alone.
Table 2 - Least Square (LS) Mean Change from Baseline in Morning Pre-dose Trough FEV1 (mL) at Week 24 in Trial 1 and Trial 2 (Intent-to-Treat Population)
Treatment | N | Trough FEV1 (mL) at Week 24 | ||
---|---|---|---|---|
Difference from | ||||
Placebo* LS Mean (95% CI) |
Glycopyrrolate 18 mcg BID* LS Mean (95% CI) |
Formoterol Fumarate 9.6 mcg BID* LS Mean (95% CI) |
||
Trial 1 | ||||
BEVESPI AEROSPHERE |
429 | N=161 150 mL (114, 186) |
N=344 59 mL (31, 88) |
N=367 64 mL (36, 92) |
Trial 2 | ||||
BEVESPI AEROSPHERE |
433 | N=170 103 mL (67, 140) |
N=367 54 mL (25, 83) |
N=350 56 mL (27, 85) |
N = Number in the intent to treat population
*The placebo, glycopyrrolate and formoterol fumarate comparators used the same inhaler and excipients as BEVESPI AEROSPHERE.
KEY CONCEPT
In both trials, BEVESPI AEROSPHERE demonstrated a larger increase in mean change from baseline in trough FEV1 at week 24 relative to placebo, glycopyrrolate alone, and formoterol fumarate alone.
With the limited data available, there were consistent improvements in trough FEV1 with respect to age, sex, degree of airflow limitation, GOLD stage, smoking status, or inhaled corticosteroid use.
In Trials 1 and 2, serial spirometric evaluations were performed throughout the 12-hour dosing interval in a subset of subjects (n=718 and n=585, respectively) at Day 1 and Week 12. Results from Trial 1 are shown in Figure 3. In Trial 2, the results for BEVESPI AEROSPHERE in FEV1 AUC0-12h were similar to those observed in Trial 1.
Figure 3 - Mean Change from Baseline in FEV1 over Time at Day 1 and Week 12 (Trial 1)
Day 1
KEY CONCEPT
This figure shows serial spirometric evaluations throughout the 12-hour dosing interval on day 1 in a subset of patients in Trial 1. Similar results were obtained in Trial 2.
Week 12
KEY CONCEPT
This figure shows serial spirometric evaluations throughout the 12-hour dosing interval at week 12 in a subset of patients in Trial 1. Similar results were obtained in Trial 2.
BEVESPI AEROSPHERE induced an onset of bronchodilation at 5 minutes after the first dose.
In both trials, peak FEV1 was defined as the maximum FEV1 recorded within 2 hours after the dose of trial medication. The mean peak FEV1 improvement from baseline with BEVESPI AEROSPHERE compared with placebo at Week 24 was 291 mL (95% CI: 252, 331) and 267 mL (95% CI: 226, 308) in Trial 1 and Trial 2, respectively. BEVESPI AEROSPHERE demonstrated an onset of bronchodilatory treatment effect at 5 minutes after the first dose based on a mean increase in FEV1 compared to placebo of 187 mL (95% CI: 168, 205) and 186 mL (95% CI: 164, 207) in Trial 1 and Trial 2, respectively. In both Trial 1 and 2, subjects treated with BEVESPI AEROSPHERE used less daily rescue albuterol compared to subjects treated with placebo.
The St. George’s Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2. In Trial 1, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) was 37%, 30%, 35%, and 28% for BEVESPI AEROSPHERE, glycopyrrolate, formoterol fumarate, and placebo, respectively, with odds ratios of 1.4 (95% CI: 1.1, 1.8), 1.1 (95% CI: 0.9, 1.5), and 1.5 (95% CI: 1.1, 2.1), for BEVESPI AEROSPHERE vs. glycopyrrolate, BEVESPI AEROSPHERE vs. formoterol fumarate, and BEVESPI AEROSPHERE vs. placebo, respectively. In Trial 2, the trends were similar, with odds ratios of 1.2 (95% CI: 0.9, 1.6), 1.3 (95% CI: 1.0, 1.7), and 1.3 (95% CI: 0.9, 1.8), for BEVESPI AEROSPHERE vs. glycopyrrolate, BEVESPI AEROSPHERE vs. formoterol fumarate, and BEVESPI AEROSPHERE vs. placebo, respectively.
FOR YOUR CLARIFICATION
The St. George’s Respiratory Questionnaire (SGRQ) is not routinely used in clinical practice, but is commonly used as an efficacy endpoint in clinical trials. It is composed of 2 parts, and measures the degree of health impairment in patients with asthma and COPD. Part 1 aims to assess the patient’s perception of his/her recent respiratory symptoms, and part 2 provides activity and impact scores. Taken together, parts 1 and 2 combine to produce a total score. Each question is weighted; higher scores represent greater impairment, whereas lower scores represent less impairment.
KEY TERM
The SGRQ responder rate is expressed as the percentage of patients who obtained an improvement in SGRQ score of 4 or more. A mean change of 4 units in the total score is also known as the "minimally important difference" and is associated with slightly efficacious treatment.
16 HOW SUPPLIED/STORAGE AND HANDLING
ORGANIZATION OF THE PI
Section 16 of the full PI is the How Supplied/Storage and Handling section. It contains information about the strength or potency of the dosage form, the units in which the dosage form is available, appropriate information regarding dosage forms including shape, color, coating, scoring, and imprinting, and any special handling or storage conditions.
SECTION 16 SUMMARY
Key considerations when using BEVESPI AEROSPHERE include:
Each canister contains 120 inhalations
The BEVESPI AEROSPHERE actuator should not be used with any other inhalation drug product
BEVESPI AEROSPHERE should be discarded when the dose indicator display window shows “0” or 3 months 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°–25°C
(68°–77°F); excursions permitted to 15°–30°C (59°–86°F)The canister should be at room temperature before use
Shake well before use
Keep out of reach of children
CONTENTS UNDER PRESSURE
Do not puncture
Do not use or store near heat or open flame
Exposure to temperatures above 49°C (120°F) may cause bursting
Never throw canister into fire or incinerator
Avoid spraying in eyes
BEVESPI AEROSPHERE Inhalation Aerosol is supplied as a pressurized aluminum canister with an attached dose indicator, a white plastic actuator and mouthpiece, and an orange dust cap. Each 120 inhalation canister has a net fill weight of 10.7 grams. Each canister is packaged in a foil pouch with desiccant sachet and is placed into a carton. Each carton contains one canister and a Medication Guide (NDC 0310-4600-12).
The BEVESPI AEROSPHERE canister should only be used with the BEVESPI AEROSPHERE actuator, and the BEVESPI 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, even though the canister may not feel completely empty. BEVESPI AEROSPHERE should be discarded when the dose indicator display window shows zero or 3 months 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°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP].
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 flame. Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into fire or incinerator. Avoid spraying in eyes.
17 PATIENT COUNSELING INFORMATION
ORGANIZATION OF THE PI
Section 17 of the full PI is the Patient Counseling Information section. It contains information necessary for the patient to use the drug effectively and safely.
SECTION 17 SUMMARY
In this section, health care providers are reminded to review the following important topics with all patients prescribed BEVESPI AEROSPHERE:
Asthma-related death
Not for acute symptoms
Do not use additional long-acting beta2-agonists
Paradoxical bronchospasm
Risks associated with beta2-agonist therapy
Worsening of narrow-angle glaucoma
Worsening of urinary retention
Instructions for administering BEVESPI AEROSPHERE
These topics are more extensively described in previous sections of the PI.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)
Asthma-Related Death: Inform patients that LABAs, such as formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE, increase the risk of asthma-related death. BEVESPI AEROSPHERE is not indicated for the treatment of asthma.
Not for Acute Symptoms: Inform patients that BEVESPI AEROSPHERE is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise them to treat acute symptoms with a rescue inhaler such as albuterol. Provide patients with such medicine and instruct them in how it should be used.
Instruct patients to seek medical attention immediately if they experience any of the following:
Symptoms get worse
Need for more inhalations than usual of their rescue inhaler
Patients should not stop therapy with BEVESPI AEROSPHERE without physician/provider guidance since symptoms may recur after discontinuation.
Do Not Use Additional Long-Acting Beta2-Agonists: Instruct patients to not use other medicines containing a LABA. Patients should not use more than the recommended dose of BEVESPI AEROSPHERE.
Instruct patients who have been taking inhaled, short-acting beta2-agonists on a regular basis to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.
Paradoxical Bronchospasm: As with other inhaled medicines, BEVESPI AEROSPHERE can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue BEVESPI AEROSPHERE.
Risks Associated With Beta2-Agonist Therapy: Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
Worsening of Narrow Angle Glaucoma: Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
Worsening of Urinary Retention: Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
Instructions for Administering BEVESPI AEROSPHERE
KEY CONCEPT
Because BEVESPI AEROSPHERE Inhalation Aerosol is AstraZeneca’s first FDA-approved LAMA/LABA in a pMDI, it is important to carefully review this section of the PI to familiarize yourself with the key considerations for properly administering BEVESPI AEROSPHERE.
Please refer to The Instructions for Use for BEVESPI AEROSPHERE for more details.
It is important for patients to understand how to correctly administer BEVESPI AEROSPHERE [see Instructions for Use].
Inform patients to use 2 inhalations of BEVESPI AEROSPHERE orally twice daily (2 inhalations in the morning and 2 inhalations in the evening).
Instruct patients to prime BEVESPI AEROSPHERE before using it for the first time. Instruct patients to prime BEVESPI AEROSPHERE by releasing 4 sprays into the air away from their face, shaking well before each spray. Inform patients that BEVESPI AEROSPHERE must be re-primed when the inhaler has not been used for more than 7 days. Instruct patients to re-prime BEVESPI AEROSPHERE by releasing 2 sprays into the air away from their face, shaking well before each spray.
Inform patients that it is very important to clean BEVESPI AEROSPHERE 1 time each week so that medicine will not build up and block the spray through the mouthpiece [see Instructions for Use]. Instruct patients to clean BEVESPI AEROSPHERE by taking the canister out of the actuator, running warm water through the actuator, and allowing the actuator to air-dry overnight. Instruct patients to insert the canister back into the actuator after it is dry, and to re-prime BEVESPI AEROSPHERE. Instruct patients to re-prime BEVESPI AEROSPHERE by releasing 2 sprays into the air away from their face, shaking well before each spray.
Inform patients that if they miss a dose of BEVESPI AEROSPHERE, they should take their next dose at the usual time. Instruct patients to not use BEVESPI AEROSPHERE more often or more puffs than they have been prescribed.
Instruct patients not to spray BEVESPI AEROSPHERE in their eyes. Inform patients that if they accidentally get BEVESPI AEROSPHERE in their eyes, to rinse their eyes with water, and if redness or irritation persists, to consult their healthcare provider.
BEVESPI®, AEROSPHERE™ and BEVESPI AEROSPHERE™ are trademarks of the AstraZeneca group of companies.
©AstraZeneca 2016
Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850
By: Aventis Pharma LTD, Holmes Chapel CW48BE, United Kingdom
ATTESTATION
I attest that I have read all of the above materials.