Aclidinium Bromide

COPD

Long-term maintenance treatment of reversible bronchospasm associated with COPD, including chronic bronchitis and emphysema.1 4 11 12 13 14

Not indicated for treatment of acute episodes of bronchospasm (i.e., as rescue therapy) or acute exacerbations of COPD.9

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Sensitivity Reactions

Immediate hypersensitivity reactions may occur.1 If such a reaction occurs, discontinue drug immediately and consider alternative therapy.1

Closely monitor patients with a history of hypersensitivity reactions to atropine.1

Use with caution in patients with severe hypersensitivity to milk proteins; commercially available formulation contains lactose monohydrate (may include milk proteins).1

Acute Bronchospasm

Indicated for maintenance treatment of bronchospasm associated with COPD; do not use for treatment of acute bronchospasm (i.e., as rescue therapy).1

Paradoxical Bronchospasm

Possible paradoxical bronchospasm upon inhalation of aclidinium.1

If paradoxical bronchospasm occurs, discontinue drug immediately and consider alternative therapy.1

Ocular Effects

Use with caution in patients with acute angle-closure glaucoma.1 May worsen symptoms and signs (e.g., ocular pain or discomfort, blurred vision, visual halos, colored images in association with red eyes from conjunctival congestion and corneal edema).1 Miotic eye drops alone not considered effective treatment for this condition.1

Use care to avoid contact of aclidinium with the eyes during oral inhalation.1 (See Advice to Patients.)

GU Effects

Use with caution in patients with urinary retention.1 May worsen symptoms and signs (e.g., urinary retention, dysuria) associated with prostatic hyperplasia or bladder neck obstruction.1 (See Advice to Patients.)

Cardiovascular Effects

No effect on QT interval observed in healthy individuals.1 15 Clinically important effects on cardiac rhythm (24-hour Holter monitoring) not observed in patients with COPD.1

Specific Populations

Category C.1

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

Safety and efficacy not established.1

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 3

Pharmacokinetics not evaluated.1

No clinically important differences in pharmacokinetics in patients with mild, moderate, or severe renal impairment compared with those with normal renal function.1

Common Adverse Effects

Headache,1 nasopharyngitis,1 cough.1

Metabolized primarily by hydrolysis; occurs chemically and enzymatically via esterases.1

Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11.1

Specific Drugs

Absorption

Bioavailability

Following oral inhalation, absolute bioavailability is approximately 6%.1 Peak plasma concentrations following oral inhalation are attained within 10 minutes and then decline rapidly.1 2 3

Onset

Following oral inhalation, bronchodilation evident within 10 minutes.14

Duration

Bronchodilation generally persists for 12 hours.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Elimination

Metabolism

Hydrolyzed rapidly and extensively to alcohol and dithienylglycolic acid derivatives (pharmacologically inactive).1 2 3 Hydrolysis occurs chemically and enzymatically via esterases.1

Elimination Route

Approximately 0.1% of dose excreted in urine following oral inhalation.1 3

Half-life

Effective half-life: 5–8 hours following oral inhalation.1

Special Populations

No clinically important differences in pharmacokinetics based on age or renal function (including mild, moderate, or severe renal impairment).1 Hepatic impairment not expected to influence pharmacokinetics.1

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.

Pharmacodynamics

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

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.

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

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.

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 [see DRUG INTERACTIONS].

Specific Populations

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 [Use In Specific Populations].

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 [see Use in Specific Populations].

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 [see Use in Specific Populations].

Clinical Studies

Chronic Obstructive Pulmonary Disease (COPD)

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).

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).

Figure 1: Change from baseline in FEV1Over Time (prior to and after administration of study drug) at Week 1 in Trial A

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).

Table 2: Change from Baseline in Trough FEV1 (L) at Week 12

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 in Figure 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.

Figure 2: Mean FEV1 Over Time (prior to and after administration of study drug) on Day 1 and Week 12 in Subset of Patients Participating in the 12 hours Serial Spirometry Substudy for Trial B (a 3-month Placebo-Controlled Study)

Mean peak improvements in FEV1, for TUDORZA PRESSAIR 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 TUDORZA PRESSAIR used less daily rescue albuterol during the trial compared to patients treated with placebo.

TUDORZA® PRESSAIR®
(TU-door-za PRESS-air)
(aclidinium bromide) Inhalation Powder

For Oral Inhalation Only

What is TUDORZA PRESSAIR?

TUDORZA PRESSAIR is a prescription medicine used long term, 2 times each day to treat symptoms of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. You may start to feel like it is easier to breathe on the first day, but it may take longer for you to feel the full effects of the medicine. TUDORZA PRESSAIR works best and may help make it easier to breathe when you use it every day.

TUDORZA PRESSAIR is not a rescue medicine and should not be used for treating sudden breathing problems. Your doctor may give you other medicine to use for sudden breathing problems.

It is not known if TUDORZA PRESSAIR is safe and effective in children.

Who should not use TUDORZA PRESSAIR?

Do not use TUDORZA PRESSAIR if you:

• have a severe allergy to milk proteins. Ask your healthcare provider if you are not sure.
• are allergic to aclidinium bromide or any of the ingredients in TUDORZA PRESSAIR. See “What are the ingredients in TUDORZA PRESSAIR?” below for a complete list of ingredients.

What should I tell my doctor before using TUDORZA PRESSAIR?

Before you use TUDORZA PRESSAIR, tell your doctor about all your medical conditions, including if you:

• have eye problems, especially glaucoma. TUDORZA PRESSAIR may make your glaucoma worse.
• have prostate or bladder problems, or problems passing urine. TUDORZA PRESSAIR may make these problems worse.
• are pregnant or plan to become pregnant. It is not known if TUDORZA PRESSAIR can harm your unborn baby.
• are breast-feeding or plan to breast-feed. TUDORZA PRESSAIR may pass into your breast milk. You and your doctor should decide if you will take TUDORZA PRESSAIR.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines and eyedrops, vitamins, and herbal supplements.

TUDORZA PRESSAIR and certain other medicines may interact with each other causing serious side effects. Especially tell your doctor if you take anticholinergics (including Tiotropium, Ipratropium) or atropine. Ask your doctor or pharmacist for a list of these medicines if you are not sure.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist each time you get a new medicine.

How should I use TUDORZA PRESSAIR?

• See the step-by-step instructions for using TUDORZA PRESSAIR at the end of this Patient Information.
• Use TUDORZA PRESSAIR exactly as prescribed.
• The usual dose of TUDORZA PRESSAIR is one oral inhalation 2 times a day. Each dose should be about 12 hours apart.
• If you miss a dose, just skip the dose. Take your next dose at your usual time. Do not take 2 doses at one time.

TUDORZA PRESSAIR does not relieve sudden symptoms of COPD. Always have a rescue inhaler medicine with you to treat sudden symptoms. If you do not have a rescue inhaler medicine, call your doctor to have one prescribed for you.

Do not use TUDORZA PRESSAIR more often than prescribed or take more medicine than prescribed for you.

• Call your doctor or get emergency medical care right away if:
  • your breathing problems worsen with TUDORZA PRESSAIR
  • you need to use your rescue inhaler medicine more often than usual
  • your rescue inhaler medicine does not work as well for you at relieving symptoms

What are the possible side effects of TUDORZA PRESSAIR?

TUDORZA PRESSAIR can cause serious side effects including:

• sudden shortness of breath immediately after use of TUDORZA PRESSAIR. If you have this symptom, stop taking TUDORZA PRESSAIR and call your doctor right away or go to the nearest hospital emergency room.
• new or worsened increased pressure in your eyes (acute narrow-angle glaucoma). Acute narrow-angle glaucoma can lead to permanent loss of vision if not treated. Symptoms of acute narrow-angle glaucoma may include:
  • eye pain or discomfort
  • seeing halos or bright colors around lights
  • blurred vision
  • nausea or vomiting
  • red eyes

Using only eyedrops to treat these symptoms may not work. If you have these symptoms, stop taking TUDORZA PRESSAIR and call your doctor right away.

• new or worsened urinary retention. Urinary retention can be caused by blockage in your bladder or, if you are a male, a larger than normal prostate. Symptoms of urinary retention may include:
  • difficulty urinating
  • urinating frequently
  • urination in a weak stream or drips
  • painful urination

If you have these symptoms of urinary retention, stop taking TUDORZA PRESSAIR and call your doctor right away.

• serious allergic reactions. Symptoms of a serious allergic reaction may include:
  • swelling of the face, lips, tongue, or throat
  • hives
  • breathing problems
  • rash
  • itching

If you have these symptoms, stop taking TUDORZA PRESSAIR and call your doctor or go to the nearest hospital emergency room right away.

The most common side effects of TUDORZA PRESSAIR include headache, common cold symptoms, or cough.

If your COPD symptoms worsen over time do not increase your dose of TUDORZA PRESSAIR, instead call your doctor.

Tell your doctor if you get any side effect that bothers you or does not go away. These are not all the possible side effects with TUDORZA PRESSAIR. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA-1088.

How should I store TUDORZA PRESSAIR?

• Store TUDORZA PRESSAIR at room temperature between 68°F to 77°F (20° to 25°C) in the protective pouch. Do not open the sealed pouch until you are ready to use a dose of TUDORZA PRESSAIR. Once a sealed pouch is opened, start using your TUDORZA PRESSAIR. 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 TUDORZA PRESSAIR in a dry place.
• Do not store the inhaler on a vibrating surface.

Keep TUDORZA PRESSAIR and all medicines out of the reach of children.

General information about the safe and effective use of TUDORZA PRESSAIR

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use TUDORZA PRESSAIR for a condition for which it was not prescribed. Do not give TUDORZA PRESSAIR to other people even if they have the same symptoms that you have. It may harm them.

This patient leaflet summarizes the most important information about TUDORZA PRESSAIR. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about TUDORZA PRESSAIR that is written for health professionals.

For more information, go to www.tudorza.com, or call 1-800-236-9933.

What are the ingredients in TUDORZA PRESSAIR?

Active ingredient: aclidinium bromide

Inactive ingredient: lactose monohydrate

This Patient Information has been approved by the U.S. Food and Drug Administration.

Instructions for Use

TUDORZA® PRESSAIR®
(TU-door-za PRESS-air)
(aclidinium bromide inhalation powder)

FOR ORAL INHALATION ONLY

Read this Instructions for Use before you start using TUDORZA PRESSAIR and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

Your TUDORZA PRESSAIR INHALER:

When you are ready to use TUDORZA PRESSAIR for the first time, remove the TUDORZA PRESSAIR inhaler from the pouch. To remove the inhaler from the pouch, tear along the “notch.” The pouch may then be discarded.

Look at the parts of the inhaler so you become familiar with them. (See Figure A)

Figure A

Taking a dose from the TUDORZA PRESSAIR Inhaler requires you to press, release, and inhale. See the step-by-step instructions for using TUDORZA PRESSAIR below.

How to prepare and use your TUDORZA PRESSAIR Inhaler

Step 1. Remove the protective cap by lightly squeezing the arrows marked on each side of the cap and pulling outwards. (See Figure B)

Figure B

• Look to see that nothing is blocking the mouthpiece.

Step 2. Hold the TUDORZA PRESSAIR inhaler with the mouthpiece facing you, but not inside your mouth. The green button should be facing straight up.(See Figure C)

Figure C

Step 3. Before you put the inhaler into your mouth, press the green button all the way down.(See Figure D)

• Then release the green button.(See Figure E)
• Do not continue to hold the green button down.

Figure D and Figure E

Step 4. Stop and Check the Control Window to make sure your dose is ready for inhalation. Look to see if the colored control window has changed from red (See Figure F), to green (See Figure G)

• The green control window tells you that your medicine is ready for inhalation. (See Figure G)
• If the control window stays red (See Figure F), repeat the Press and Release actions in Step 3 until the control window is green.

Figure F and Figure G

Now the dose is ready to be inhaled.

Step 5. Before you put the inhaler into your mouth, breathe out completely. Do not breathe out into the inhaler.

• Put your lips tightly around the mouthpiece of the TUDORZA PRESSAIR inhaler. Breathe in quickly and deeply through your mouth. (See Figure H). This quick, deep breath makes sure that you get enough of the medication from the inhaler into your lungs.
• Breathe in until you hear a “click” sound. Keep breathing in, even after you have heard the inhaler “click” to be sure you get the full dose.
• Do not hold down the green button while you are breathing in. (See Figure H)
• Do not hold down the green button while you are breathing in. (See Figure I)

Figure H and Figure I

Step 6. Remove the TUDORZA PRESSAIR inhaler from your mouth and hold your breath for as long as is comfortable (See Figure J), then breathe out slowly through your nose.

Figure J

Some people may taste the medicine during their inhalation. Do not take an extra dose even if you do not taste anything after inhaling.

Step 7. Stop and Check the Control Window. Make sure you have used your TUDORZA PRESSAIR inhaler correctly.

• Look at the control window to see if it has turned to red (See Figure K) from green (See Figure L). If the window is red you have inhaled your full dose of medicine correctly.

Figure K and Figure L

• If the colored control window is still green, repeat Step 5.
• If the window still does not change to red, you may have forgotten to release the green button before inhaling or may not have inhaled correctly. If that happens repeat Step 5 again.
• Make sure you have released the green button and take a quick and deep breath in through the mouthpiece.
• If you are unable to inhale correctly after several attempts, call your doctor.

Step 8. Once the window has turned red, place the protective cap back onto the inhaler by pressing it back onto the mouthpiece. (See Figure M)

Figure M

Additional information about the safe and effective use of TUDORZA PRESSAIR inhaler

• The “click” sound and colored control window:
• The “click” that you hear while inhaling tells you that you are using the TUDORZA PRESSAIR inhaler correctly.
• When you use the inhaler correctly the colored control window changes from green to red.
• Each time you are ready to use the TUDORZA PRESSAIR inhaler again, you will need to make sure the inhaler is ready by pressing and releasing the green button as seen in Step 3. When you press and release the green button the colored control window will change from red to green.

Helpful Tips for Using Tudorza Pressair

The Tudorza Pressair inhaler comes ready-to-use with 3 steps for twice-daily dosing. Remember to Press, Release and Inhale every time you use Tudorza. PRESS the green button all the way down

RELEASE the green button completely

INHALE quickly and deeply keeping a tight seal with your lips around the mouthpiece

You know you are getting the full dose of medicine when you hear the click while inhaling and see the inhaler's window change colors from green to red.

For more information about TUDORZA PRESSAIR and a video demonstration on how to use TUDORZA PRESSAIR, go to www.tudorza.com.

When should you get a new TUDORZA PRESSAIR inhaler?

• The TUDORZA PRESSAIR inhaler has a dose indicator to show you how many doses are left in your inhaler. Each TUDORZA PRESSAIR inhaler has 60 doses of medicine.
  • When you start using the inhaler for the first time you will see the number 60 in the dose indicator.
  • You will see the number of doses count down in the dose indicator as you use the inhaler. The dose indicator moves down slowly, displaying intervals of 10 (60, 50, 40, 30, 20, 10, 0).
  • When a red band begins to appear in the dose indicator (See Figure N), this means you are nearing your last dose and should obtain a new PRESSAIR inhaler.

Figure N

• You should discard the inhaler and start a new one when
  • the marking “0” with the red background shows in the middle of the dose indicator (See Figure O), or
  • the device locks out (See Figure P), or
  • 45 days after you took the inhaler out of the sealed pouch, whichever comes first.

Figure O

Figure P

• If your TUDORZA PRESSAIR inhaler appears to be damaged or if you lose the cap, your inhaler should be replaced.
• You do not need to clean your TUDORZA PRESSAIR inhaler. If you wish to clean it, wipe the outside of the mouthpiece with a dry tissue or paper towel. Do not use water to clean your TUDORZA PRESSAIR inhaler, as this may damage your medicine.

Questions and Answers about your TUDORZA PRESSAIR Inhaler

This Instructions for Use has been approved by the U.S. Food and Drug Administration.