Prescription Drug Information: BEVESPI AEROSPHERE

BEVESPI AEROSPHERE- glycopyrrolate and formoterol fumarate aerosol, metered
AstraZeneca Pharmaceuticals LP

1 INDICATIONS AND USAGE

BEVESPI AEROSPHERE is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

Limitations 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)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage and Administration

The recommended dosage of BEVESPI AEROSPHERE is glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg (administered as two inhalations of BEVESPI AEROSPHERE [glycopyrrolate/formoterol fumarate 9 mcg/4.8 mcg]) twice daily in the morning and in the evening by oral inhalation. Do not take more than two inhalations twice daily.

2.2 Preparation

Prime BEVESPI AEROSPHERE before using for the first time. Priming BEVESPI AEROSPHERE is essential to ensure appropriate drug content in each actuation. 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.

2.3 Dose Counter

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.

3 DOSAGE FORMS AND STRENGTHS

Inhalation aerosol: pressurized metered dose inhaler that delivers 9 mcg of glycopyrrolate and 4.8 mcg of formoterol fumarate per inhalation.

4 CONTRAINDICATIONS

BEVESPI AEROSPHERE is contraindicated in:

use of a long-acting beta2 -adrenergic agonist (LABA), including formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE, without an inhaled corticosteroid, in patients with asthma [see Warnings and Precautions (5.1)]. BEVESPI AEROSPHERE is not indicated for the treatment of asthma.
patients with hypersensitivity to glycopyrrolate, formoterol fumarate, or to any component of the product [see Warnings and Precautions (5.5)].

5 WARNINGS AND PRECAUTIONS

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

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 Contraindications (4)].
Use of LABA as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.
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.
Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

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.

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.

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.

5.3 Avoid Excessive Use of BEVESPI and Avoid 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)].

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.

5.5 Hypersensitivity Reactions including Anaphylaxis

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.

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.

5.7 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.

5.8 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.

5.9 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.

5.10 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.

6 ADVERSE REACTIONS

The following adverse reactions are described in greater detail elsewhere in the labeling:

Paradoxical bronchospasm [see Warnings and Precautions (5.4)]
Hypersensitivity reactions including Anaphylaxis [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 (5.7)]
Worsening of urinary retention [see Warnings and Precautions (5.8)]

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.

24-Week Trials

The 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.

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 (n=1036) %

Glycopyrrolate 18 mcg BID (n=890) %

Formoterol Fumarate 9.6 mcg BID (n=890) %

Placebo (n=443) %

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

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.

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).

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