Glycopyrrolate and formoterol fumarate

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Glycopyrrolate and formoterol fumarate
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Allison Tu [2]

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Black Box Warning

ASTHMA-RELATED DEATH
See full prescribing information for complete Boxed Warning.
  • 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 glycopyrrolate and formoterol fumarate.
  • The safety and efficacy of glycopyrrolate and formoterol fumarate in patients with asthma have not been established. Glycopyrrolate and formoterol fumarate is not indicated for the treatment of asthma.

Overview

Glycopyrrolate and formoterol fumarate is a combination of an anticholinergic and a long-acting beta2-adrenergic agonist that is FDA approved for the treatment of airflow obstruction in patients with chronic obstructive pulmonary disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include urinary tract infection and cough.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Chronic Obstructive Pulmonary Disease

Glycopyrrolate and formoterol fumarate 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. Glycopyrrolate and formoterol fumarate is not indicated for the relief of acute bronchospasm or for the treatment of asthma.

Dosing information

  • Glycopyrrolate and formoterol fumarate (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.
  • 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.
  • Glycopyrrolate and formoterol fumarate contains 28 or 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. Glycopyrrolate and formoterol fumarate should be discarded when the dose indicator display window shows zero.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Glycopyrrolate and formoterol fumarate in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Glycopyrrolate and formoterol fumarate in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Glycopyrrolate and formoterol fumarate FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Glycopyrrolate and formoterol fumarate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Glycopyrrolate and formoterol fumarate in pediatric patients.

Contraindications

Warnings

ASTHMA-RELATED DEATH
See full prescribing information for complete Boxed Warning.
  • 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 glycopyrrolate and formoterol fumarate.
  • The safety and efficacy of glycopyrrolate and formoterol fumarate in patients with asthma have not been established. Glycopyrrolate and formoterol fumarate is not indicated for the treatment of asthma.
  • 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 glycopyrrolate and formoterol fumarate.
    • No trial adequate to determine whether the rate of asthma-related deaths is increased in patients treated with glycopyrrolate and formoterol fumarate has been conducted. The safety and efficacy of glycopyrrolate and formoterol fumarate in patients with asthma have not been established. Glycopyrrolate and formoterol fumarate is not indicated for the treatment of asthma.
  • Deterioration of Disease and Acute Episodes
    • Glycopyrrolate and formoterol fumarate should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Glycopyrrolate and formoterol fumarate has not been studied in patients with acutely deteriorating COPD. The use of glycopyrrolate and formoterol fumarate in this setting is inappropriate.
    • Glycopyrrolate and formoterol fumarate should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate, 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 glycopyrrolate and formoterol fumarate, 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 glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate beyond the recommended dose is not appropriate in this situation.
  • Excessive Use of glycopyrrolate and formoterol fumarate and Use with Other Long-Acting Beta2-Agonists
    • As with other inhaled medicines containing beta2-agonists, glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate should not use another medicine containing a LABA for any reason.
  • Paradoxical Bronchospasm
    • As with other inhaled medicines, glycopyrrolate and formoterol fumarate can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with glycopyrrolate and formoterol fumarate, it should be treated immediately with an inhaled, short-acting bronchodilator, glycopyrrolate and formoterol fumarate should be discontinued immediately, and alternative therapy should be instituted.
  • Immediate Hypersensitivity Reactions
  • Cardiovascular Effects
  • Coexisting Conditions
  • 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. 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 glycopyrrolate and formoterol fumarate in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.
  • Worsening of Narrow-Angle Glaucoma
  • Worsening of Urinary Retention

Adverse Reactions

Clinical Trials Experience

LABAs, such as formoterol fumarate, one of the active ingredients in glycopyrrolate and formoterol fumarate, increase the risk of asthma-related death. Glycopyrrolate and formoterol fumarate is not indicated for the treatment of asthma.

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 glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate. 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 glycopyrrolate and formoterol fumarate 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: glycopyrrolate and formoterol fumarate, glycopyrrolate 18 mcg, formoterol fumarate 9.6 mcg, or placebo twice daily or active control.
This image is provided by the National Library of Medicine.

Other adverse reactions defined as events with an incidence of >1% but less than 2% with glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate, 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).

Postmarketing Experience

There is limited information regarding Glycopyrrolate and formoterol fumarate Postmarketing Experience in the drug label.

Drug Interactions

No formal drug interaction studies have been performed with glycopyrrolate and formoterol fumarate.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Teratogenic Effects:

There are no adequate and well-controlled trials of glycopyrrolate and formoterol fumarate or its individual components, glycopyrrolate and formoterol fumarate, in pregnant women. Because animal reproduction studies are not always predictive of human response, glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate.

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).
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glycopyrrolate and formoterol fumarate in women who are pregnant.

Labor and Delivery

There are no well-controlled human trials that have investigated the effects of glycopyrrolate and formoterol fumarate on preterm labor or labor at term. Because beta2-agonists may potentially interfere with uterine contractility, glycopyrrolate and formoterol fumarate should be used during labor only if the potential benefit justifies the potential risk.

Nursing Mothers

It is not known whether glycopyrrolate and formoterol fumarate is excreted in human milk. Because many drugs are excreted in human milk and because formoterol fumarate, one of the active ingredients in glycopyrrolate and formoterol fumarate, has been detected in the milk of lactating rats, caution should be exercised when glycopyrrolate and formoterol fumarate is administered to a nursing woman. Since there are no data from controlled trials on the use of glycopyrrolate and formoterol fumarate by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue glycopyrrolate and formoterol fumarate, taking into account the importance of glycopyrrolate and formoterol fumarate to the mother.

Pediatric Use

Glycopyrrolate and formoterol fumarate is not indicated for use in children. The safety and effectiveness of glycopyrrolate and formoterol fumarate in the pediatric population have not been established.

Geriatic Use

Based on available data, no adjustment of the dosage of glycopyrrolate and formoterol fumarate in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

The confirmatory trials of glycopyrrolate and formoterol fumarate 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.

Gender

There is no FDA guidance on the use of Glycopyrrolate and formoterol fumarate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Glycopyrrolate and formoterol fumarate with respect to specific racial populations.

Renal Impairment

Formal pharmacokinetic studies using glycopyrrolate and formoterol fumarate 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, glycopyrrolate and formoterol fumarate should be used if the expected benefit outweighs the potential risk.

Hepatic Impairment

Formal pharmacokinetic studies using glycopyrrolate and formoterol fumarate 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.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Glycopyrrolate and formoterol fumarate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Glycopyrrolate and formoterol fumarate in patients who are immunocompromised.

Administration and Monitoring

Administration

Priming glycopyrrolate and formoterol fumarate is essential to ensure appropriate drug content in each actuation. Prime glycopyrrolate and formoterol fumarate before using for the first time. To prime glycopyrrolate and formoterol fumarate, release 4 sprays into the air away from the face, shaking well before each spray. Glycopyrrolate and formoterol fumarate must be re-primed when the inhaler has not been used for more than 7 days. To re-prime glycopyrrolate and formoterol fumarate, release 2 sprays into the air away from the face, shaking well before each spray.

Glycopyrrolate and formoterol fumarate (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.

Monitoring

There is limited information regarding Glycopyrrolate and formoterol fumarate Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Glycopyrrolate and formoterol fumarate and IV administrations.

Overdosage

No cases of overdose have been reported with glycopyrrolate and formoterol fumarate. Glycopyrrolate and formoterol fumarate contains both glycopyrrolate and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to glycopyrrolate and formoterol fumarate. Treatment of overdosage consists of discontinuation of glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate, 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.

Pharmacology

There is limited information regarding Glycopyrrolate and formoterol fumarate Pharmacology in the drug label.

Mechanism of Action

Glycopyrrolate and formoterol fumarate contains both glycopyrrolate and formoterol fumarate. The mechanism of action described below for the individual components apply to glycopyrrolate and formoterol fumarate. 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.

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.

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. 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.

Structure

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:
This image is provided by the National Library of Medicine.

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:

This image is provided by the National Library of Medicine.

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).

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 glycopyrrolate and formoterol fumarate 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.
  • 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 glycopyrrolate and formoterol fumarate and glycopyrrolate/formoterol fumarate 72/19.2 mcg, respectively.

Chronic Obstructive Pulmonary Disease

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.

  • Absorption
    • Glycopyrrolate: Following inhaled administration of glycopyrrolate and formoterol fumarate in subjects with COPD, Cmax occurred at 5 minutes. Steady state is expected to be achieved within 2-3 days of repeated dosing of glycopyrrolate and formoterol fumarate and the extent of exposure is approximately 2.3 times higher than after the first dose.
    • Formoterol Fumarate: Following inhaled administration of glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate and the extent of exposure is approximately 1.5 times higher than after the first dose.
  • 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.
    • 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
  • 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.
  • 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:

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of glycopyrrolate and formoterol fumarate which contains glycopyrrolate and formoterol fumarate. The data described below for the individual components apply to glycopyrrolate and formoterol fumarate.

  • 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).

Clinical Studies

The safety and efficacy of glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate 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.

  • Dose-Ranging Trials
    • Dose selection for glycopyrrolate and formoterol fumarate 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.
    • 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).
        This image is provided by the National Library of Medicine.
      • 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 open-label ipratropium bromide inhalation aerosol administered four times daily. 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).
        This image is provided by the National Library of Medicine.
      • 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.
  • Confirmatory Trials
    • The clinical development program for glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate 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%).
    • Trial 1 and Trial 2 evaluated glycopyrrolate and 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 glycopyrrolate and formoterol fumarate with glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg was assessed to evaluate the contribution of the individual components to glycopyrrolate and formoterol fumarate. In both trials, glycopyrrolate and formoterol fumarate 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).
      This image is provided by the National Library of Medicine.
    • 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 glycopyrrolate and formoterol fumarate in FEV1 AUC0-12h were similar to those observed in Trial 1.
      This image is provided by the National Library of Medicine.
    • 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 glycopyrrolate and formoterol fumarate 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. glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate, 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 glycopyrrolate and formoterol fumarate vs. glycopyrrolate, glycopyrrolate and formoterol fumarate vs. formoterol fumarate, and glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate vs. glycopyrrolate, glycopyrrolate and formoterol fumarate vs. formoterol fumarate, and glycopyrrolate and formoterol fumarate vs. placebo, respectively.

How Supplied

  • Glycopyrrolate and formoterol fumarate 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 (NDC 0310-4600-12) and each 28 inhalation canister (institutional pack) has a net fill weight of 5.9 grams (NDC 0310-4600-39). 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.
  • The glycopyrrolate and formoterol fumarate canister should only be used with the glycopyrrolate and formoterol fumarate actuator, and the glycopyrrolate and formoterol fumarate 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. Glycopyrrolate and formoterol fumarate 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”).

Storage

Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

For best results, the canister should be at room temperature before use. Shake well before using. Keep out of reach of children.

Images

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Package and Label Display Panel

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Patient Counseling Information

  • Asthma-Related Death:
    • Inform patients that LABAs, such as formoterol fumarate, one of the active ingredients in glycopyrrolate and formoterol fumarate, increase the risk of asthma-related death. Glycopyrrolate and formoterol fumarate is not indicated for the treatment of asthma.
  • Not for Acute Symptoms:
    • Inform patients that glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate.
    • 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:
  • Risks Associated With Beta2-Agonist Therapy:
  • Worsening of Narrow Angle Glaucoma:
  • Worsening of Urinary Retention:
  • Instructions for Administering glycopyrrolate and formoterol fumarate:
    • It is important for patients to understand how to correctly administer glycopyrrolate and formoterol fumarate.
    • Inform patients to use 2 inhalations of glycopyrrolate and formoterol fumarate orally twice daily (2 inhalations in the morning and 2 inhalations in the evening).
    • Instruct patients to prime glycopyrrolate and formoterol fumarate before using it for the first time. Instruct patients to prime glycopyrrolate and formoterol fumarate by releasing 4 sprays into the air away from their face, shaking well before each spray. Inform patients that glycopyrrolate and formoterol fumarate must be re-primed when the inhaler has not been used for more than 7 days. Instruct patients to re-prime glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate 1 time each week so that medicine will not build up and block the spray through the mouthpiece. Instruct patients to clean glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate. Instruct patients to re-prime glycopyrrolate and formoterol fumarate 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 glycopyrrolate and formoterol fumarate, they should take their next dose at the usual time. Instruct patients to not use glycopyrrolate and formoterol fumarate more often or more puffs than they have been prescribed.
    • Instruct patients not to spray glycopyrrolate and formoterol fumarate in their eyes. Inform patients that if they accidentally get glycopyrrolate and formoterol fumarate in their eyes, to rinse their eyes with water, and if redness or irritation persists, to consult their healthcare provider.

Precautions with Alcohol

Alcohol-Glycopyrrolate and formoterol fumarate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Glycopyrrolate and formoterol fumarate Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Glycopyrrolate and formoterol fumarate Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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