Aclidinium bromide

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# Overview
Aclidinium bromide is an anticholinergic that is FDA approved for the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.   Common adverse reactions include headache, nasopharyngitis and cough.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- TUDORZA PRESSAIR (aclidinium bromide inhalation powder) is indicated for the long-term, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
- The recommended dose of TUDORZA PRESSAIR is one oral inhalation of 400 mcg, twice daily.

## Off-Label Use and Dosage (Adult)

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

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

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Aclidinium bromide in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

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

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Aclidinium bromide in pediatric patients.

# Contraindications
- None.

# Warnings

### Precautions
- Not for Acute Use
- TUDORZA PRESSAIR 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 TUDORZA PRESSAIR, may cause paradoxical bronchospasm. If this occurs, treatment with TUDORZA PRESSAIR should be stopped and other treatments considered.
- Worsening of Narrow-Angle Glaucoma
- TUDORZA PRESSAIR 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
- TUDORZA PRESSAIR 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 TUDORZA PRESSAIR. If such a reaction occurs, therapy with TUDORZA PRESSAIR 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 TUDORZA PRESSAIR. In addition, TUDORZA PRESSAIR 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.
- TUDORZA PRESSAIR 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 TUDORZA PRESSAIR 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 TUDORZA PRESSAIR group in the two 3-month and one 6-month placebo-controlled trials where the rates in the TUDORZA PRESSAIR group exceeded placebo.
- 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.
- TUDORZA PRESSAIR 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 TUDORZA PRESSAIR 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 Postmarketing Experience of Aclidinium bromide 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 TUDORZA PRESSAIR.
- 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 TUDORZA PRESSAIR with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- 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. TUDORZA PRESSAIR 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) . However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD . 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 . 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 , and decreased fetal body weights were observed at approximately 2,300 times the RHDD . These fetal findings were observed in the presence of maternal toxicity.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aclidinium bromide in women who are pregnant.

### Labor and Delivery
- The effect of TUDORZA PRESSAIR on labor and delivery is unknown. TUDORZA PRESSAIR 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 TUDORZA PRESSAIR on breast-fed infants. Caution should be exercised when TUDORZA PRESSAIR is administered to nursing women.

### Pediatric Use
- TUDORZA PRESSAIR 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 TUDORZA PRESSAIR in pediatric patients have not been established.

### Geriatic Use
- Of the 636 COPD patients exposed to TUDORZA PRESSAIR 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 TUDORZA PRESSAIR, no adjustment of dosage in geriatric patients is warranted.

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

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

### Renal Impairment
- The pharmacokinetics of TUDORZA PRESSAIR 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 TUDORZA PRESSAIR, no adjustment of dosage in renally impaired subjects is warranted.

### Hepatic Impairment
- The effects of hepatic impairment on the pharmacokinetics of TUDORZA PRESSAIR were not studied.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aclidinium bromide in women of reproductive potentials and males.

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

# Administration and Monitoring

### Administration
- Inhalational

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

# IV Compatibility
There is limited information regarding IV Compatibility of Aclidinium bromide in the drug label.

# Overdosage

## Acute Overdose
- No case of overdose has been reported in clinical studies with TUDORZA PRESSAIR. There were no systemic anticholinergic or other adverse effects following a single inhaled dose of up to 6,000 mcg aclidinium bromide (7.5 times the RHDD) in 16 healthy volunteers.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Aclidinium bromide in the drug label.

# 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
- TUDORZA PRESSAIR 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-Azoniabicyclooctane, 3--1-(3-phenoxypropyl)-, bromide, (3R)-. The structural formula is:
- 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.
- TUDORZA PRESSAIR is a breath-actuated multi-dose dry powder inhaler. Each actuation of TUDORZA PRESSAIR 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 TUDORZA PRESSAIR 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 TUDORZA PRESSAIR 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
- 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 .
- 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 . These adverse fertility effects were observed in the presence of paternal toxicity as evidenced by mortality and decreased body weight gain. However, there were no effects on mating index and sperm number and morphology. In the separate fertility assessments (treated males mated with untreated females; treated females mated with untreated males), no effect was observed in male and female rats at inhaled doses of 1.9 and 0.8 mg/kg/day, respectively .

# Clinical Studies
- The TUDORZA PRESSAIR 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 TUDORZA PRESSAIR 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 TUDORZA PRESSAIR 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the TUDORZA PRESSAIR 400 mcg twice daily dose (Figure 1).
- 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 TUDORZA PRESSAIR 400 mcg twice daily (636 patients) and placebo (640 patients). TUDORZA PRESSAIR 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 (Table 2).
- 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 inFigure 2. 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.

# How Supplied
- TUDORZA PRESSAIR(aclidinium bromide inhalation powder) 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses (NDC 0456-0800-60) and 30 metered doses (NDC 0456-0800-31).
- 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 and Handling
- Store TUDORZA PRESSAIR in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).
- 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.

## Storage
There is limited information regarding Aclidinium bromide Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Instructions for Administering TUDORZA PRESSAIR
- It is important for patients to understand how to correctly use TUDORZA PRESSAIR.
- 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 TUDORZA PRESSAIR 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 TUDORZA PRESSAIR can cause paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue TUDORZA PRESSAIR.
- 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 bromide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- TUDORZA PRESSAIR

# Look-Alike Drug Names
There is limited information regarding Aclidinium bromide Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price