Consumer medicine information

Incruse ellipta

Umeclidinium

BRAND INFORMATION

Brand name

Incruse Ellipta Powder for inhalation

Active ingredient

Umeclidinium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Incruse ellipta.

What is in this leaflet

Please read this leaflet carefully before you start using INCRUSE ELLIPTA.

This leaflet answers some common questions about INCRUSE ELLIPTA.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking INCRUSE ELLIPTA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What INCRUSE ELLIPTA is used for

INCRUSE ELLIPTA is used to treat chronic obstructive pulmonary disease (COPD). To use INCRUSE ELLIPTA, you breathe it into your lungs through your mouth using the ELLIPTA inhaler.

Chronic obstructive pulmonary disease (COPD) is a long-term condition that slowly gets worse. Symptoms include shortness of breath, cough, chest discomfort and coughing up mucus.

INCRUSE ELLIPTA contains the active ingredient umeclidinium.

Umeclidinium belongs to a group of medicines called bronchodilators. Umeclidinium helps open the airways and make it easier for air to get in and out of the lungs. This will help relieve symptoms of COPD, a serious, long-term lung disease characterised by breathing difficulties. When INCRUSE ELLIPTA is used regularly, it can help to control the breathing difficulties related to your disease and minimise the effects of the disease on your everyday life.

INCRUSE ELLIPTA should not be used to relieve a sudden attack of breathlessness or wheezing. If you get this sort of attack you must use a quick-acting inhaler (such as VENTOLIN®).

Your doctor may have prescribed INCRUSE ELLIPTA for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

This medicine is not expected to affect your ability to drive a car or operate machinery.

INCRUSE ELLIPTA should not be given to children or adolescents below the age of 18 years.

Before you use INCRUSE ELLIPTA

When you must not use it

Don't use INCRUSE ELLIPTA

  • if you are allergic (hypersensitive) to lactose or milk protein
  • if you are allergic (hypersensitive) to umeclidinium, or any of the ingredients of INCRUSE ELLIPTA (listed at the end of this leaflet).

If you think either of these applies to you, don't use INCRUSE ELLIPTA until you have checked with your doctor.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing, coughing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching, redness or hives on the skin
  • suddenly feeling weak or light headed (may lead to collapse or loss of consciousness)

INCRUSE ELLIPTA contains lactose.

If you have been diagnosed with an intolerance to some sugars, or to milk protein, talk to your doctor before you use INCRUSE ELLIPTA.

If you are pregnant, if you think you may be pregnant or if you are planning to have a baby, don't use INCRUSE ELLIPTA without asking your doctor.

Your doctor will consider the benefit to you and the risk to your baby of taking INCRUSE ELLIPTA while you are pregnant.

If you are breast-feeding, check with your doctor before you take INCRUSE ELLIPTA.

It is not known whether the ingredients of INCRUSE ELLIPTA can pass into breast milk.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to use it

Talk to your doctor before you use INCRUSE ELLIPTA:

  • if you have asthma (do not use INCRUSE ELLIPTA to treat asthma)
  • if you have heart problems or high blood pressure
  • if you have an eye problem called narrow-angle glaucoma
  • if you have an enlarged prostate, difficulty passing urine or a blockage in your bladder.

Check with your doctor before you use INCRUSE ELLIPTA if you think any of these apply to you.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

Your doctor can discuss with you the risks and benefits involved.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

How to use INCRUSE ELLIPTA

Follow all directions given to you by your doctor or pharmacist carefully.

If you do not understand the instructions in the user leaflet, ask your doctor or pharmacist for help.

How much to use

Always use INCRUSE ELLIPTA exactly as your doctor has told you to. Check with your doctor, nurse or pharmacist if you're not sure.

The dose is one inhalation of INCRUSE ELLIPTA once daily at the same time each day.

Don't use more than your doctor tells you to use. The dose should not exceed one inhalation per day.

How to use the inhaler

The full instructions for using INCRUSE ELLIPTA are given on a leaflet inside the pack.

INCRUSE ELLIPTA is ready to use straight away. No preparation or checks of the inhaler are required.

Do not open INCRUSE ELLIPTA until you are ready to use it for the first time.

After using INCRUSE ELLIPTA, you may clean the mouthpiece, using a dry tissue, before you close the cover. Do not immerse INCRUSE ELLIPTA in water.

When to use it

Use INCRUSE ELLIPTA regularly.

It is very important that you use INCRUSE ELLIPTA every day, as instructed by your doctor. This will help to keep you free of symptoms throughout the day and night.

If you feel you are getting breathless or wheezy more often than normal, or if you are using your quick-acting inhaler more than usual, see your doctor.

How long to use it

Don't stop INCRUSE ELLIPTA without medical advice.

Use INCRUSE ELLIPTA for as long as your doctor recommends. It will only be effective as long as you are using it. Don't stop unless your doctor advises you to, even if you feel better.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and use your next dose when you are meant to. Otherwise, use it as soon as you remember, then go back to using it as you would normally.

Don't take an extra dose to make up for a missed dose.

If you are not sure what to do, ask your doctor or pharmacist.

If you become wheezy or breathless, or develop any other symptoms of an asthma attack, use your quick-acting inhaler (e.g. VENTOLIN), then seek medical advice.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

In Australia, immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, if you think that you or anyone else may have taken too much INCRUSE ELLIPTA. Do this even if there are no signs of discomfort or poisoning.

In New Zealand, immediately telephone your doctor or the National Poisons Centre (telephone 0800 POISON or 0800 764 766) if you think that you or anyone else may have taken too much INCRUSE ELLIPTA.

If you accidentally take a larger dose of INCRUSE ELLIPTA than your doctor has instructed, you may notice that your heart is beating faster than usual, you have a dry mouth or have problems with your vision and focusing on objects.

While you are using INCRUSE ELLIPTA

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking INCRUSE ELLIPTA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor should give you a personal Action Plan to help manage your COPD. This plan will include what medicines to take regularly to control your COPD, as well as what "reliever" medicines to use when you have sudden attacks of breathlessness or wheezing.

Things you must not do

Do not take INCRUSE ELLIPTA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine without checking with your doctor.

Do not take any other medicines for your breathing problems without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how INCRUSE ELLIPTA affects you.

Side effects

Like all medicines, INCRUSE ELLIPTA can cause side effects, although not everybody gets them.

If you get tightness of the chest, coughing, wheezing or breathlessness immediately after using your INCRUSE ELLIPTA, stop using it immediately, and seek medical help immediately.

If you experience eye pain or discomfort, blurred vision, visual halos or coloured images in association with red, swollen or watery eyes, these could be signs and symptoms of acute narrow-angle glaucoma. Seek medical help immediately if any of these signs or symptoms develop.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Common side effects

These may affect up to 1 in 10 people:

  • painful and frequent urination (may be signs of a urinary tract infection)
  • feeling of pressure or pain in the cheeks and forehead (may be signs of inflammation of the sinuses called sinusitis)
  • combination of sore throat and runny nose
  • faster heart beat
  • cough
  • infection of the upper airways
  • taste disturbance.

Uncommon side effects

These may affect up to 1 in 100 people:

  • irregular heartbeat
  • constipation
  • dry mouth
  • allergic reactions.

Rare side effects

These may affect up to 1 in 1000 people:

  • eye pain
  • blurred vision
  • decrease in vision or pain in your eyes due to high pressure (possible signs of glaucoma)
  • difficulties in or unable to pass urine.

If you think you are having an allergic reaction to INCRUSE ELLIPTA, stop using this medicine and tell your doctor immediately or go the accident and emergency department at your nearest hospital. Symptoms of an allergic reaction usually include some or all of the following:

  • shortness of breath
  • wheezing, coughing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash,itching, redness or hives on the skin
  • suddenly feeling weak or light headed (may lead to collapse or loss of consciousness)

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

After using INCRUSE ELLIPTA

Storage

Do not use INCRUSE ELLIPTA after the expiry date shown on the pack.

Store in the original package container in order to protect from moisture and do not open the foil lid until ready to inhale for the first time.

Safely throw away INCRUSE ELLIPTA six weeks after you open the foil tray or when your counter reads "0", whichever comes first. Write the date the inhaler should be discarded on the label in the space provided. The date should be added as soon as the inhaler has been removed from the tray.

Keep your inhaler in cool dry place where the temperature stays below 30°C.

If you store in a refrigerator allow the inhaler to return to room temperature for at least an hour before use.

Do not store INCRUSE ELLIPTA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

INCRUSE ELLIPTA is inhaled through the mouth using the ELLIPTA device. The active substance is in separate blisters in powder form inside the device. There are either 7 or 30 blisters on each strip, and so each device contains either 7 or 30 doses depending on which pack size has been given.

The ELLIPTA device itself is a plastic inhaler with a light grey body, a light green mouthpiece cover and a dose counter. It is packaged in a foil laminate tray with a peelable foil lid. The tray contains a desiccant sachet, to reduce the moisture in the packaging. Once you have opened the lid of the tray, throw the desiccant away - do not open, eat or inhale it.

Ingredients

The active ingredient in INCRUSE ELLIPTA is umeclidinium.

Each dose contains 62.5 micrograms of the active ingredient umeclidinium (as bromide).

INCRUSE ELLIPTA also contains the inactive ingredients:

  • lactose monohydrate (which contains milk proteins)
  • magnesium stearate

Supplier

INCRUSE ELLIPTA is supplied in Australia by:


GlaxoSmithKline Australia Pty Ltd
Level 4, 436 Johnston Street
Abbotsford Victoria 3067
Australia.

INCRUSE ELLIPTA is supplied in New Zealand by:


GlaxoSmithKline NZ Ltd
Private Bag 106600
Downtown
Auckland 1143
New Zealand

Where to go for further information

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition. You may also be able to find general information about your disease and its treatment from patient information groups and books, for example in public libraries.

This leaflet was prepared on 4 April 2017.

The information provided applies only to: INCRUSE® ELLIPTA®.

INCRUSE and ELLIPTA are registered trade marks of the GSK group of companies.

INCRUSE ELLIPTA:
AUST R 211601

©2017 GSK group of companies.All rights reserved.

Version 6.0



BRAND INFORMATION

Brand name

Incruse Ellipta Powder for inhalation

Active ingredient

Umeclidinium

Schedule

S4

 

1 Name of Medicine

Umeclidinium (as bromide).

2 Qualitative and Quantitative Composition

Moulded plastic device containing one foil strip of either 7 or 30 regularly distributed blisters, each containing a white powder. Each delivered dose (the dose leaving the mouthpiece of the inhaler) contains 55 micrograms umeclidinium (equivalent to 65 micrograms of umeclidinium bromide). This corresponds to a pre-dispensed dose of 62.5 micrograms of umeclidinium (equivalent to 74.2 micrograms umeclidinium bromide).
Umeclidinium bromide is slightly soluble in water and slightly soluble in methanol, ethanol, acetonitrile and propan-1-ol.

List of excipients with known effect.

Lactose monohydrate (which contains milk protein).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for inhalation.

4 Clinical Particulars

4.1 Therapeutic Indications

Incruse Ellipta is indicated as a long-term once daily maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

4.2 Dose and Method of Administration

Incruse Ellipta is for oral inhalation use only.

Adults.

Incruse Ellipta (umeclidinium 62.5 microgram) should be taken as one inhalation once daily by the orally inhaled route.
Incruse Ellipta should be taken at the same time every day.
Do not use Incruse Ellipta more than once every 24 hours.

Dosing considerations.

Incruse Ellipta should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing a long-acting muscarinic antagonist, as an overdose may result.
When beginning treatment with Incruse Ellipta, patients who have been taking inhaled, short-acting muscarinic antagonists on a regular basis (e.g. 4 times a day) should be instructed to discontinue the regular use of these drugs.
Patients should be made aware that for optimum benefit, Incruse Ellipta must be used regularly, even when asymptomatic.

Special populations.

Paediatric populations.

This product should not be used in children.

Elderly population.

No dosage adjustment is required in patients over 65 years (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Renal impairment.

No dosage adjustment is required in patients with renal impairment (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Hepatic impairment.

No dosage adjustment is required in patients with mild or moderate hepatic impairment. Incruse Ellipta has not been studied in patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

How to use Incruse Ellipta.

What is the Ellipta inhaler?

Incruse Ellipta is inhaled through the mouth using the Ellipta inhaler.
When you first use the Ellipta inhaler you do not need to check that it is working properly, and you do not need to prepare it for use in any special way. Just follow these step by step instructions.
The inhaler is packaged in a tray. Do not open the tray until you are ready to inhale a dose of your medicine. When you are ready to use your inhaler, peel back the lid to open the tray. The tray contains a desiccant sachet, to reduce moisture. Throw this desiccant sachet away - do not open, eat or inhale it.
When you take the inhaler out of the sealed tray, it will be in the 'closed' position. Do not open the inhaler until you are ready to inhale a dose of medicine. Write the "Discard by" date on the inhaler label in the space provided. The "Discard by" date is 6 weeks from the date you open the tray. After this date, the inhaler should no longer be used.
The step-by-step instructions shown below for the 30-dose (30 day supply) Ellipta inhaler also apply to the 7 dose (7 day supply) Ellipta inhaler.

Important information to read before you start.

If you open and close the cover without inhaling the medicine, you will lose the dose.
The lost dose will be securely held inside the inhaler, but it will no longer be available.
It is not possible to accidentally take extra medicine or a double dose in one inhalation. See Figure 1.

Step 1: prepare a dose.

Wait to open the cover until you are ready to take your dose. Do not shake the inhaler.
Slide the cover fully down until you hear a 'click'. See Figure 2.
Your medicine is now ready to be inhaled.
The dose counter counts down by 1 to confirm.
If the dose counter does not count down as you hear the 'click', the inhaler will not deliver medicine. Take it back to your pharmacist for advice.
Do not shake the inhaler at any time.

Step 2: Inhale your medicine.

Whilst holding the inhaler away from your mouth, breathe out as far as is comfortable.
Do not breathe out into the inhaler.
Put the mouthpiece between your lips, and close your lips firmly around it.
Do not block the air vent with your fingers. See Figure 3.
Take one long, steady, deep breath in. Hold this breath for about 3-4 seconds or for as long as is comfortable.
Remove the inhaler from your mouth.
Breathe out slowly and gently away from the mouthpiece.
You may not be able to taste or feel the medicine, even when you are using the inhaler correctly.
If you want to clean the mouthpiece, use a dry tissue, before you close the cover.

Step 3: close the inhaler.

Slide the cover upwards as far as it will go, to cover the mouthpiece.

4.3 Contraindications

Incruse Ellipta is contraindicated in patients with severe milk protein allergy or who have demonstrated hypersensitivity to either umeclidinium or any of the excipients.

4.4 Special Warnings and Precautions for Use

Asthma.

The use of Incruse Ellipta has not been studied in patients with asthma, and is not recommended in this patient population.

Deterioration of disease and acute episodes.

Incruse Ellipta is intended for the long-term maintenance treatment of COPD.
Incruse Ellipta has not been studied in subjects with acutely deteriorating COPD. The initiation of Incruse Ellipta in this setting is not appropriate.
Incruse Ellipta has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose.
When prescribing Incruse Ellipta, it is recommended the physician advise the patient to have an inhaled, short-acting beta2-agonist for treatment of acute symptoms available at all times.
COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Incruse Ellipta no longer controls symptoms of bronchoconstriction, the patient's inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of a short-acting beta2-agonist than usual to relieve symptoms, these may be markers of deterioration of disease control. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once by a physician. Increasing the daily dose of Incruse Ellipta beyond the recommended dose is not appropriate in this situation.
Exacerbations may occur during treatment with Incruse Ellipta. Patients should be advised to continue treatment and seek medical advice if COPD symptoms remain uncontrolled or worsen after initiation of therapy with Incruse Ellipta.

Paradoxical bronchospasm.

As with other inhalation therapies, administration of Incruse Ellipta may produce paradoxical bronchospasm that may be life threatening. Treatment with Incruse Ellipta should be discontinued if paradoxical bronchospasm occurs and alternative therapy instituted if necessary.

Cardiovascular effects.

Cardiovascular effects, such as cardiac arrhythmias, e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists, including Incruse Ellipta. Therefore, Incruse Ellipta should be used with caution in patients with severe cardiovascular disorders, particularly cardiac arrhythmias.

Antimuscarinic activity.

Consistent with its antimuscarinic activity, Incruse Ellipta should be used with caution in patients with narrow angle glaucoma or urinary retention. 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 coloured images in association with red eyes from conjunctival congestion and corneal oedema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

Excipients.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Incruse Ellipta.

Use in the elderly.

There are no special precautions for use in the elderly.

Paediatric use.

This product should not be used in children.

Effects on laboratory tests.

Interactions with laboratory tests have not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Clinically significant drug interactions mediated by umeclidinium at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.

Interaction with P-glycoprotein inhibitors.

Umeclidinium is a substrate of P-glycoprotein (P-gp) transporter. The effect of the P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy volunteers. No effect of verapamil was observed on umeclidinium Cmax. An approximately 1.4-fold increase in umeclidinium AUC was observed.
Based on the magnitude of these changes, no clinically relevant drug interaction is expected when umeclidinium is coadministered with P-gp inhibitors.

Interaction with CYP2D6 inhibitors.

Umeclidinium is a substrate of CYP2D6. The effect of a CYP2D6 poor metaboliser genotype on the steady-state pharmacokinetics of umeclidinium was assessed in healthy volunteers (CYP2D6 normal metabolisers and CYP2D6 poor metabolisers). No clinically meaningful difference in systemic exposure to umeclidinium (500 microgram) was observed following repeat daily inhaled dosing to normal and CYP2D6 poor metaboliser subjects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of Incruse Ellipta on human fertility. Studies in rats showed no effects of umeclidinium on male or female fertility at doses producing very large multiples of the systemic exposure in patients.
(Category B1)
There is a limited amount of data from the use of Incruse Ellipta in pregnant women. Embryofoetal development was unaffected by umeclidinium in rats treated at up to 278 microgram/kg/day by inhalation (estimated to yield 50 times the plasma AUC in patients at the maximum recommended human dose of 62.5 microgram per day) and in rabbits treated at up to 306 microgram/kg/day by inhalation or up to 180 microgram/kg/day subcutaneously (yielding 35 and ~ 200 times the plasma AUC in patients).
Incruse Ellipta should only be used during pregnancy if the expected benefit to the mother justifies the potential risk to the foetus.
It is unknown whether umeclidinium is excreted in human milk. A risk to breastfed newborns/ infants cannot be excluded.
A decision must be made whether to discontinue breastfeeding or to discontinue Incruse Ellipta therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of Incruse Ellipta on the ability to perform tasks that require judgement, motor or cognitive skills. There have been no adverse effects associated with Incruse Ellipta that would affect the ability to perform tasks that require judgement, motor or cognitive skills.

4.8 Adverse Effects (Undesirable Effects)

Umeclidinium as monotherapy.

Clinical trial data.

Table 1 shows all adverse events that occurred with a frequency of greater than 1% in either of the groups receiving Incruse Ellipta in the four 24 week well controlled studies where the rates in either of the groups receiving Incruse Ellipta exceeded placebo by greater than 1%.

52 week study.

In a long-term safety study, 336 subjects (n = 227 umeclidinium 125 microgram, n = 109 placebo) were treated for up to 52 weeks with umeclidinium 125 microgram or placebo. The demographic and baseline characteristics of the long-term safety study were similar to those of the efficacy studies. In addition to the adverse events listed in Table 3, the adverse events reported in subjects receiving umeclidinium 125 microgram with a frequency of greater than 1% and exceeding the rate in subjects receiving placebo by greater than 1% in this study were: nasopharyngitis (umeclidinium 125 microgram 9%, placebo 5%), supraventricular extrasystoles (umeclidinium 125 microgram 3%, placebo < 1%), supraventricular tachycardia (umeclidinium 125 microgram 3%, placebo < 1%), rhythm idioventricular (umeclidinium 125 microgram 2%, placebo 0%), and urinary tract infection (umeclidinium 125 microgram 2%, placebo 0%).
The safety profile of Incruse Ellipta was evaluated from 1663 patients with COPD who received doses of 62.5 microgram or greater for up to one year. This includes 576 patients who received the recommended dose of 62.5 microgram once daily.
The adverse reactions identified from the four pivotal studies and the long-term safety study (which involved 1,412 patients who received Incruse Ellipta) are presented in Table 2.
Adverse drug reactions (ADRs) are listed by MedDRA system organ class and by frequency. The following convention has been used for the classification of adverse reactions.
Very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000; very rare: < 1/10,000.

Post-marketing data.

See Table 3.

Umeclidinium in combination with ICS/ LABA.

In addition to the umeclidinium monotherapy adverse reactions reported above, adverse reactions occurring with Incruse Ellipta in combination with an ICS/ LABA (either fluticasone furoate/ vilanterol 100 microgram/25 microgram or fluticasone propionate/ salmeterol 250 microgram/50 microgram) in four 12 week studies (pooled data), at an incidence of greater than or equal to 1% and exceeding ICS/ LABA alone, were oropharyngeal pain, back pain, diarrhoea, headache and dysgeusia. The safety data for long-term use is limited given the short duration of the studies.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No data from clinical studies are available regarding overdose with Incruse Ellipta.

Symptoms and signs.

An overdose of Incruse Ellipta will likely produce signs and symptoms consistent with the known inhaled muscarinic antagonist adverse effects (e.g. dry mouth, visual accommodation disturbances and tachycardia).

Treatment.

If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Umeclidinium is a long acting muscarinic receptor antagonist (also referred to as an anticholinergic). It is a quinuclidine derivative that is a muscarinic receptor antagonist with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic acetylcholine receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in preclinical models.

Pharmacodynamic effects.

Improvement in lung function over placebo was seen at 15 minutes (the first time point assessed after dosing) and was maintained over 24 hours. There was no evidence for tachyphylaxis to the bronchodilator effect after repeated dosing of Incruse Ellipta 125 microgram for up to 52 weeks in COPD patients.
In a 24 week, placebo controlled clinical efficacy study in COPD patients Incruse Ellipta 62.5 microgram increased forced expiratory volume in one second (FEV1) after the first dose on day 1 with an improvement of 0.07 L at 15 minutes compared with placebo (p < 0.001). The increase from baseline to peak FEV1 over the first 6 hours postdose at day 1 was 0.23 L with umeclidinium 62.5 microgram compared with 0.11 L for placebo. The increase from baseline to peak FEV1 over the first 6 hours postdose at week 24 was 0.23 L with umeclidinium 62.5 microgram compared with 0.10 L for placebo.

Cardiovascular effects.

The effect of umeclidinium 500 microgram on the QT interval was evaluated in a placebo and moxifloxacin controlled QT study of 103 healthy volunteers. Following repeat doses of 500 microgram once daily for 10 days, no clinically relevant effect on prolongation of QT interval (corrected using the Fridericia method) was observed.

Clinical trials.

Placebo controlled studies.

The efficacy of Incruse Ellipta administered once daily was evaluated in two placebo controlled clinical studies, in adult patients with a clinical diagnosis of COPD; a 12 week study (AC4115408) and a 24 week study (DB2113373). In the 12 week study, Incruse Ellipta demonstrated statistically significant and clinically meaningful improvements in measures of lung function (as defined by change from baseline trough FEV1 at week 12, which was the primary efficacy endpoint compared with placebo (see Table 4). The bronchodilatory effects with Incruse Ellipta compared with placebo were evident after the first day of treatment and were maintained over the 12 week treatment period.
Incruse Ellipta demonstrated a statistically significant greater improvement from baseline in weighted mean FEV1 over 0-6 hours postdose at week 12 compared with placebo (0.17 L (p < 0.001)).
The percentage of patients receiving Incruse Ellipta that responded with a minimum clinically important difference (MCID) of ≥ 1 unit Transition Dyspnoea Index (TDI) focal score at week 12 was 38% (24/64) compared with 15% (8/53) for placebo. The odds of being a TDI responder vs. a nonresponder, was statistically significantly greater for Incruse Ellipta compared with placebo at week 12 (odds ratio 3.4 (95% CI 1.3, 8.4), p = 0.009).
Incruse Ellipta demonstrated statistically significant improvements from placebo in the change from baseline in total score at week 12 for the St. George's Respiratory Questionnaire (SGRQ), a disease specific health status measure (-7.90 units) (p < 0.001). The percentage of patients receiving Incruse Ellipta that responded with a reduction of ≥ 4 units (MCID) in SGRQ total score at week 12 was 44% (28/63) compared with 26% (14/54) for placebo. The odds of being a SGRQ responder vs. a nonresponder, was statistically significantly greater for Incruse Ellipta compared with placebo at week 12 (odds ratio 2.44 (95% CI 1.08, 5.50), p = 0.032).
In addition, patients treated with Incruse Ellipta required less rescue salbutamol over the 12 week treatment period than those treated with placebo (mean reduction of 0.7 puffs per day and the difference from placebo was statistically significant (p = 0.025)).
In the 24 week study, DB2113373, Incruse Ellipta demonstrated statistically significant improvements in lung function (as defined by change from baseline trough FEV1 at week 24, which was the primary efficacy endpoint compared with placebo (see Table 5). The bronchodilatory effects with Incruse Ellipta compared with placebo were evident after the first day of treatment and were maintained over the 24 week treatment period.
Incruse Ellipta demonstrated a statistically significant greater improvement from baseline in weighted mean FEV1 over 0-6 hours postdose at week 24 compared with placebo (0.15 L; p < 0.001).
A statistically significant improvement from placebo in the TDI focal score at week 24 was demonstrated for Incruse Ellipta (1.0 units) (p < 0.001). The percentage of patients receiving Incruse Ellipta that responded with a minimum clinically important difference (MCID) of ≥ 1 unit TDI focal score at week 24 was 53% (207/394) compared with 41% (106/260) for placebo. The odds of being a TDI responder vs. a nonresponder, was statistically significantly greater for Incruse Ellipta compared with placebo at week 24 (odds ratio 1.6 (95% CI 1.2, 2.3), p = 0.002).
A statistically significant improvement from placebo in the change from baseline in total score at week 24 for the St. George's Respiratory Questionnaire (SGRQ), a disease specific health status measure, was also demonstrated for Incruse Ellipta (-4.69 units) (p ≤ 0.001). The percentage of patients receiving Incruse Ellipta that responded with a reduction of ≥ 4 units (MCID) in SGRQ total score at week 24 was 44% (172/388) compared with 34% (86/254) for placebo. The odds of being a SGRQ responder vs. a nonresponder, was statistically significantly greater for Incruse Ellipta compared with placebo at week 24 (odds ratio 1.6 (95% CI 1.2, 2.3), p = 0.003).
Treatment with Incruse Ellipta lowered the risk of a COPD exacerbation compared with placebo (analysis of time to first exacerbation; hazard ratio 0.6, p = 0.035, risk reduction 40%).

Supporting efficacy studies.

In two 12 week, placebo controlled studies (200109 and 200110), the addition of umeclidinium to fluticasone furoate/ vilanterol (FF/VI) (100/25 microgram) once daily in adult patients with a clinical diagnosis of COPD, resulted in statistically significant improvements in the primary endpoint of trough FEV1 at day 85 compared to placebo plus FF/VI (124 mL (95% CI 93, 154, p < 0.001) and 122 mL (95% CI 91, 152, p < 0.001)).
Improvements in SGRQ at week 12 were not statistically significant (200109) or clinically relevant (200109 and 200110).
The population studied in these trials included patients with moderate to very severe COPD. Subjects were required to have a pre and postsalbutamol FEV1/ forced vital capacity (FVC) ratio of < 0.70 and a pre and postsalbutamol FEV1 of < 70% of predicted normal values. All subjects had a modified Medical Research Council dyspnoea scale score ≥ 2.
In study 200109 no patients were GOLD stage 1, 40% were GOLD stage 2, 46% were GOLD stage 3, and 14% GOLD stage 4.
In study 200110, no patients were GOLD stage 1, 48% were GOLD stage 2, 41% were GOLD stage 3 and 11% were GOLD stage 4.
In two 12 week, placebo controlled studies (AC4116135 and AC4116136), the addition of umeclidinium to fluticasone propionate/ salmeterol (FSC) (250/50 microgram) twice daily in adult patients with a clinical diagnosis of COPD, resulted in statistically significant improvements in the primary endpoint of trough FEV1 at day 85 compared to placebo plus FSC (147 mL (95% CI 107, 187, p < 0.001) and 127 mL (95% CI 89, 164, p < 0.001)).
Improvements in SGRQ at week 12 were not statistically significant or clinically relevant for both studies (AC4116135 and AC4116136).
The population studied in these trials included patients with moderate to very severe COPD. Subjects were required to have a pre and postsalbutamol FEV1/ forced vital capacity (FVC) ratio of < 0.70 and a pre and postsalbutamol FEV1 of < 70% of predicted normal values. All subjects had a modified Medical Research Council dyspnoea scale score ≥ 2.
In study AC4116135, no patients were GOLD stage 1, 46% were GOLD stage 2, 44% were GOLD stage 3 and 11% were GOLD stage 4.
In study AC4116136 no patients were GOLD stage 1, 40% were GOLD stage 2, 48% were GOLD stage 3, and 12% GOLD stage 4.
The short duration of these four studies and limited number of exacerbation events, preclude any conclusion regarding additional effect of Incruse on COPD exacerbation rate.

5.2 Pharmacokinetic Properties

Absorption.

Following inhaled administration of umeclidinium in healthy volunteers, Cmax occurred at 5 to 15 minutes. The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 7 to 10 days with 1.5 to 2-fold accumulation. Umeclidinium systemic exposure following inhaled administration was dose proportional.

Distribution.

Following intravenous administration to healthy subjects, the mean volume of distribution was 86 litres. In vitro plasma protein binding in human plasma was on average 89%.

Metabolism.

In vitro studies showed that umeclidinium is metabolised principally by the enzyme P450 CYP2D6 and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Excretion.

Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours postdose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the drug related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male subjects, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours postdose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours, with 3% to 4% drug excreted unchanged in urine at steady state.

Special patient populations.

Elderly.

A population pharmacokinetic analysis showed that pharmacokinetics of umeclidinium are similar between COPD patients 65 years and older and those younger than 65 years of age.

Renal impairment.

Subjects with severe renal impairment (creatinine clearance < 30 mL/min) showed no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC), and no evidence of altered protein binding between subjects with severe renal impairment and healthy volunteers.

Hepatic impairment.

Subjects with moderate hepatic impairment showed no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC), and no evidence of altered protein binding between subjects with moderate hepatic impairment and healthy volunteers. Incruse Ellipta has not been evaluated in subjects with severe hepatic impairment.

Other patient characteristics.

A population pharmacokinetic analysis showed that no dose adjustment is required for umeclidinium based on the effect of age, race, gender, inhaled corticosteroid use, or weight. A study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium.

5.3 Preclinical Safety Data

Genotoxicity.

Umeclidinium was not genotoxic in a standard battery of studies, comprising bacterial mutation assays, the mouse lymphoma tk assay and the rat bone marrow micronucleus test.

Carcinogenicity.

Umeclidinium was not carcinogenic in 2 year inhalation studies in mice or rats at doses yielding systemic exposure levels (plasma AUC) up to 26 or 22 times the human clinical exposure of umeclidinium at the maximum recommended dose of 62.5 microgram per day in the respective species.

6 Pharmaceutical Particulars

6.1 List of Excipients

Incruse Ellipta contains the excipients lactose monohydrate (which contains milk protein) and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.
If stored in the refrigerator, allow the inhaler to return to room temperature for at least 1 hour before use.
Following removal from the tray, the product may be stored for a maximum period of 6 weeks.
Write the date the inhaler should be discarded on the label in the space provided. The date should be added as soon as the inhaler has been removed from the tray.

6.5 Nature and Contents of Container

Incruse Ellipta is a moulded plastic inhaler with a light grey body, a light green mouthpiece cover and a dose counter, packed in a foil tray which contains a desiccant sachet. The tray is sealed with a peelable foil lid. The inhaler contains an aluminium foil laminate strip of either 30 or 7 regularly distributed blisters, each containing a white powder.
Not all pack sizes may be distributed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical name.

The chemical name of umeclidinium bromide is 1-azoniabicyclo[2.2.2]octane, 4-(hydroxydiphenylmethyl)- 1-[2-(phenylmethoxy)ethyl]-, bromide (1:1).

Chemical formula.

Umeclidinium bromide: C29H34BrNO2.

Chemical structure.

Umeclidinium bromide:

CAS number.

Umeclidinium bromide: 869113-09-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes