Aclidinium

Aclidinium
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: Sree Teja Yelamanchili, MBBS [2]

Disclaimer

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Overview

Aclidinium is an antimuscarinic and bronchodilator that is FDA approved for the treatment of long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.. Common adverse reactions include headache, cough, and nasopharyngitis..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• The recommended dose of Aclidinium bromide is one oral inhalation of 400 mcg, twice daily.

• Inhalation Powder- Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Aclidinium in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Aclidinium in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Aclidinium 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 Aclidinium in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Aclidinium in pediatric patients.

Contraindications

None.

Warnings

Not for Acute Use

Aclidinium bromide is intended as a twice-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy).

Paradoxical Bronchospasm

Inhaled medicines, including Aclidinium bromide, may cause paradoxical bronchospasm. If this occurs, treatment with Aclidinium bromide should be stopped and other treatments considered.

Worsening of Narrow-Angle Glaucoma

Aclidinium bromide 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.

Worsening of Urinary Retention

Aclidinium bromide should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of Aclidinium bromide. If such a reaction occurs, therapy with Aclidinium bromide should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to Aclidinium bromide. In addition, Aclidinium bromide should be used with caution in patients with severe hypersensitivity to milk proteins.

Adverse Reactions

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

3-Month and 6-Month Trials

• Aclidinium bromide was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily.

• The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.

TABLE 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the Aclidinium bromide group in the two 3-month and one 6-month placebo-controlled trials where the rates in the Aclidinium bromide group exceeded placebo.

This image is provided by the National Library of Medicine.

In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were diabetes mellitus, dry mouth, 1st degree AV block, osteoarthritis, cardiac failure, and cardio-respiratory arrest.

Long-term Safety Trials

Aclidinium bromide was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe COPD. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.

Postmarketing Experience

There is limited information regarding Aclidinium Postmarketing Experience in the drug label.

Drug Interactions

In vitro studies suggest limited potential for CYP450-related metabolic drug interactions, thus no formal drug interaction studies have been performed with Aclidinium bromide.

Sympathomimetics, Methylxanthines, Steroids

In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of COPD including sympathomimetics (short-acting beta2 agonists), methylxanthines, and oral and inhaled steroids showed no increases in adverse drug reactions.

Anticholinergics

There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of Aclidinium bromide with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Teratogenic effects

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. Adverse development effects were observed in rats and rabbits exposed to aclidinium bromide. Aclidinium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of aclidinium bromide on embryo-fetal development were examined in rats and rabbits. No evidence of structural alterations was observed in rats exposed during the period of organogenesis at approximately 15 times the recommended human daily dose (RHDD) [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.

No evidence of structural alterations was observed in Himalayan rabbits exposed during the period of organogenesis at approximately 20 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. However, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. These fetal findings were observed in the presence of maternal toxicity.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aclidinium in women who are pregnant.

Labor and Delivery

• The effect of Aclidinium bromide on labor and delivery is unknown.
• Aclidinium bromide should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.

Nursing Mothers

• Aclidinium bromide is excreted into the milk of lactating female rats, and decreased pup weights were observed.
• Excretion of aclidinium into human milk is probable.
• There are no human studies that have investigated the effects of Aclidinium bromide on breast-fed infants.
• Caution should be exercised when Aclidinium bromide is administered to nursing women.

Pediatric Use

• Aclidinium bromide is approved for use in the maintenance treatment of bronchospasm associated with COPD.
• COPD does not normally occur in children.
• The safety and effectiveness of Aclidinium bromide in pediatric patients have not been established.

Geriatic Use

• Of the 636 COPD patients exposed to Aclidinium bromide 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age.
• No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
• Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
• Based on available data for Aclidinium bromide, no adjustment of dosage in geriatric patients is warranted.

Gender

There is no FDA guidance on the use of Aclidinium with respect to specific gender populations.

Race

There is no FDA guidance on the use of Aclidinium with respect to specific racial populations.

Renal Impairment

• The pharmacokinetics of Aclidinium bromide were investigated in subjects with normal renal function and in subjects with mild, moderate and severe renal impairment.
• No clinically significant differences in aclidinium pharmacokinetics were noted between these populations.
• Based on available data for Aclidinium bromide, no adjustment of dosage in renally impaired subjects is warranted.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of Aclidinium bromide were not studied.

Females of Reproductive Potential and Males

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

Immunocompromised Patients

There is no FDA guidance one the use of Aclidinium in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Aclidinium Administration in the drug label.

Monitoring

There is limited information regarding Aclidinium Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Aclidinium and IV administrations.

Overdosage

There is limited information regarding Aclidinium overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Mechanism of Action

• Aclidinium bromide 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 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 acetylcholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours.
• The clinical relevance of these findings is unknown.
• The bronchodilation following inhalation of aclidinium bromide is predominantly a site-specific effect.

Structure

Aclidinium bromide consists of a dry powder formulation of aclidinium bromide for oral inhalation only.

Aclidinium bromide, the active component of TUDORZA PRESSAIR is an anticholinergic with specificity for muscarinic receptors. Aclidinium bromide is a synthetic, quaternary ammonium compound, chemically described as 1-Azoniabicyclo[2.2.2]octane, 3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-. The structural formula is:

This image is provided by the National Library of Medicine.

Aclidinium bromide is a white powder with a molecular formula of C26H30NO4S2Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol.

Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler. Each actuation of Aclidinium bromide provides a metered dose of 13 mg of the formulation which contains lactose monohydrate (which may contain milk proteins) as the carrier and 400 mcg of aclidinium bromide. This results in delivery of 375 mcg aclidinium bromide from the mouthpiece, based onin vitro testing at an average flow rate of 63 L/min with constant volume of 2 L. The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow rate and inspiratory time. The PRESSAIR inhaler delivers the target dose at flow rates as low as 35 L/min. Based on a study in adult patients with moderate (N=24) and severe (N=24) COPD the mean peak inspiratory flow (PIF) was 95.3 L/min (range: 54.6 to 129.4 L/min) and 88.7 L/min (range: 72.0 to 106.4 L/min) respectively.

Pharmacodynamics

Cardiovascular Effects

• In a thorough QT Study, 200 mcg and 800 mcg Aclidinium bromide was administered to healthy volunteers once daily for 3 days; no effects on prolongation of QT interval were observed using QTcF heart-rate correction methods.
• Additionally, the effect of Aclidinium bromide on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr Holter monitoring.
• No clinically significant effects on cardiac rhythm were observed.

Pharmacokinetics

Absorption

• The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers.
• Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.

Distribution

• Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.

Metabolism

• Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases.
• Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
• Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.

Elimination

• Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%.
• Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium.
• Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces.
• The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis.
• After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.

Drug Interactions

• Formal drug interaction studies were not performed.
• In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose.
• Therefore, it is unlikely that aclidinium bromide causes CYP450 related drug interactions.

Specific Populations

Elderly Patients

The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients.

Renal Impairment

The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe renal impairment. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide.
• No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Recommended Human Daily Dose (RHDD), respectively, based on summed AUCs of aclidinium bromide and its metabolites].

• Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.

• Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the RHDD based on summed AUCs of aclidinium bromide and its metabolites].

Clinical Studies

Chronic Obstructive Pulmonary Disease (COPD)=

The Aclidinium bromide clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).

Dose-ranging trial

Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had a forced expiratory volume in one second (FEV1) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced vital capacity (FEV1/FVC) of less than 0.7. Trial A included Aclidinium bromide doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough FEV1 and serial FEV1 in patients treated with the Aclidinium bromide 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the Aclidinium bromide 400 mcg twice daily dose.

This image is provided by the National Library of Medicine.

Confirmatory trials

Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with COPD. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.

These clinical trials evaluated Aclidinium bromide 400 mcg twice daily (636 patients) and placebo (640 patients). Aclidinium bromide 400 mcg resulted in statistically significantly greater bronchodilation as measured by change from baseline in morning pre-dose FEV1 at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials.

This image is provided by the National Library of Medicine.

Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3-month trials (Trial B) are displayed. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3- or 6-month treatment period.

This image is provided by the National Library of Medicine.

Mean peak improvements in FEV1, for Aclidinium bromide relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with Aclidinium bromide used less daily rescue albuterol during the trial compared to patients treated with placebo.

How Supplied

Aclidinium bromide inhalation powder 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses and 30 metered doses.

The active ingredient is administered using a multi-dose dry powder inhaler, PRESSAIR®, which delivers 60 doses or 30 doses of aclidinium bromide powder for oral inhalation. The PRESSAIR inhaler is a white and green colored device and is comprised of an assembled plastic dosing mechanism with a dose indicator, a drug-product storage unit containing the drug-product formulation, and a mouthpiece covered by a green protective cap. The inhaler should be discarded when the marking “0” with a red background shows in the middle of the dose indicator or when the device locks out, whichever comes first.

Storage

Store Aclidinium bromide in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F)[see USP Controlled Room Temperature].

The PRESSAIR inhaler should be stored inside the sealed pouch and only be opened immediately before use.

Discard the PRESSAIR inhaler 45 days after opening the pouch, after the marking “0” with a red background shows in the middle of the dose indicator, or when the device locks out, whichever comes first.

Keep out of reach of children.

Images

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Package and Label Display Panel

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Patient Counseling Information

Instructions for Administering Aclidinium bromide

It is important for patients to understand how to correctly use Aclidinium bromide. Inform patients that if they miss a dose, they should take their next dose at the usual time; they should not take 2 doses at one time.

Acute Bronchospasm

Instruct patients that Aclidinium bromide is a twice daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

Paradoxical Bronchospasm

Inform patients that Aclidinium bromide can cause paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Aclidinium bromide.

Visual Effects

Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eyedrops alone are not considered to be effective treatment.

• Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.

Urinary Retention

Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.

Precautions with Alcohol

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

Brand Names

• Aclidinium bromide

Look-Alike Drug Names

There is limited information regarding Aclidinium 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.