Consumer medicine information

Anoro Ellipta

Umeclidinium; Vilanterol

BRAND INFORMATION

Brand name

Anoro Ellipta

Active ingredient

Umeclidinium; Vilanterol

Schedule

What is in this leaflet

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

This leaflet answers some common questions about ANORO 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 ANORO 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 ANORO ELLIPTA is used for

ANORO ELLIPTA is used to treat chronic obstructive pulmonary disease (COPD). To use ANORO 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.

ANORO ELLIPTA contains two active ingredients: umeclidinium bromide and vilanterol trifenatate.

Umeclidinium bromide and vilanterol trifenatate belongs to a group of medicines called bronchodilators. Umeclidinium and vilanterol work together to help open the airways and make it easier for air to get in and out of the lungs. This will help relieve symptoms of COPD. When ANORO 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.

ANORO 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 ANORO 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.

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

Before you use ANORO ELLIPTA

When you must not use it

Don't use ANORO ELLIPTA

if you are allergic (hypersensitive) to lactose or milk protein
if you are allergic (hypersensitive) to umeclidinium bromide, vilanterol trifenatate or any other ingredients of ANORO ELLIPTA (listed at the end of this leaflet).

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

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

ANORO 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 ANORO ELLIPTA.

If you are pregnant, if you think you may be pregnant or if you are planning to have a baby, don't use ANORO ELLIPTA without asking your doctor. Your doctor will consider the benefit to you and the risk to your baby of taking ANORO ELLIPTA while you are pregnant.

If you are breast-feeding, check with your doctor before you take ANORO ELLIPTA. It is not known whether the ingredients of ANORO 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 ANORO ELLIPTA:

if you have asthma (do not use ANORO 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 ANORO 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.

Some medicines may affect how ANORO ELLIPTA works, or make it more likely that you'll have side effects. These include:

medicines called beta blockers, to treat high blood pressure or other heart problems
ketoconazole, to treat fungal infections.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to use ANORO 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 ANORO 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 every day at the same time of day.

How to use the inhaler

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

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

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

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

When to use it

Use ANORO ELLIPTA regularly. It is very important that you use ANORO 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 (such as VENTOLIN) more than usual, see your doctor.

How long to use it

Don't stop ANORO ELLIPTA without medical advice.

Use ANORO 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 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 ANORO ELLIPTA.

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 ANORO ELLIPTA. Do this even if there are no signs of discomfort or poisoning.

If you accidentally take a larger dose of ANORO ELLIPTA than your doctor has instructed, you may notice that your heart is beating faster than usual, you feel shaky or have a headache.

While you are using ANORO 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 ANORO 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.

Things you must not do

Do not take ANORO 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 or lower the dosage 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 ANORO ELLIPTA affects you.

Side effects

Like all medicines, ANORO 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 ANORO ELLIPTA, stop using it immediately, and seek medical help immediately.

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:

sore throat with or without runny nose
cough
constipation
dry mouth
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)
pain and irritation in the back of the mouth and throat
infection of the upper airways.

Uncommon side effects

These may affect up to 1 in 100 people:

irregular heartbeat
faster heart beat
awareness of heart beat (palpitations)
anxiety
tremor
taste disturbance
muscle spasms
rash (allergic reactions).

Rare side effects

These may affect up to 1 in 1,000 people:

allergic reactions
immediate breathing difficulties and wheezing
decrease in vision or pain in your eyes due to high pressure (possible signs of glaucoma)
blurred vision
increase of the measured eye pressure
difficulties passing urine (urinary retention)
pain or discomfort when passing urine (dysuria)
hoarseness.

If you think you are having an allergic reaction to ANORO 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:

wheezing, coughing
swelling of the lips/mouth, tongue or throat
difficulty in breathing
hay fever lumpy rash ("hives") or redness
fainting, suddenly feeling weak or light headed

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 ANORO ELLIPTA

Storage

Do not use ANORO 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 ANORO 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 ANORO 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

ANORO ELLIPTA is inhaled through the mouth using the ELLIPTA device. The active substances are 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 you have been given.

The ELLIPTA device itself is a plastic inhaler with a light grey body, a red 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 ingredients in ANORO ELLIPTA are umeclidinium (as bromide) and vilanterol (as trifenatate).

Each dose contains 62.5 micrograms of the active ingredient umeclidinium. Each dose also contains 25 micrograms of the active ingredient vilanterol.

ANORO ELLIPTA also contains the inactive ingredients:

lactose monohydrate (which contains milk proteins)
magnesium stearate.

Supplier

Your ANORO ELLIPTA is supplied in Australia by:

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

Your ANORO ELLIPTA is supplied in New Zealand by:

GlaxoSmithKline NZ Limited
Private Bag 106600
Downtown
Auckland
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: ANORO® ELLIPTA®.

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

ANORO ELLIPTA 62.5/25 micrograms - AUST R 207529

Version 7.0

Published by MIMS August 2017

BRAND INFORMATION

Brand name

Anoro Ellipta

Active ingredient

Umeclidinium; Vilanterol

Schedule

1 Name of Medicine

Umeclidinium (as bromide)/ vilanterol (as trifenatate).

2 Qualitative and Quantitative Composition

Moulded plastic device containing two foil strips of either 7 or 30 regularly distributed blisters, each containing a white powder formulation of 74.2 micrograms of umeclidinium bromide (equivalent to 62.5 micrograms of umeclidinium) and 25 micrograms of vilanterol (as trifenatate). Each delivered dose (the dose leaving the mouthpiece of the inhaler) contains 55 micrograms umeclidinium (equivalent to 65 micrograms of umeclidinium bromide) and 22 micrograms vilanterol (as trifenatate).

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

Anoro 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

Anoro Ellipta is for oral inhalation use only.

Adults.

Anoro Ellipta (umeclidinium/ vilanterol 62.5/25 micrograms) should be taken as one inhalation once daily by the orally inhaled route.
Anoro Ellipta should be taken at the same time everyday.
Do not use Anoro Ellipta more than once every 24 hours.

Children.

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. Anoro Ellipta has not been studied in patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

How to use Anoro Ellipta.

What is the Ellipta inhaler?

Anoro 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.

See Figure 4.

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

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Asthma.

Anoro Ellipta should not be used in patients with asthma since it has not been studied in this patient population.

Deterioration of disease.

Anoro Ellipta is intended for the long-term maintenance treatment of COPD. It should not be used for the relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled short acting bronchodilator. Increasing use of short acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.

Paradoxical bronchospasm.

As with other inhalation therapies, administration of Anoro Ellipta may produce paradoxical bronchospasm that may be life threatening. Treatment with Anoro 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 sympathomimetic agents and muscarinic receptor antagonists, including Anoro Ellipta. Therefore, Anoro Ellipta should be used with caution in patients with severe cardiovascular disease.

Antimuscarinic activity.

Consistent with its antimuscarinic activity, Anoro 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 this medicinal product.

Use in the elderly.

There are no special precautions for use in the elderly.

Paediatric use.

Anoro Ellipta 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 and vilanterol at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.

Interaction with beta-blockers.

Beta-adrenergic blockers may weaken or antagonise the effect of beta₂-agonists, such as vilanterol trifenatate. Concurrent use of either nonselective or selective beta-adrenergic blockers should be avoided unless there are compelling reasons for their use.

Interaction with CYP3A4 inhibitors.

Vilanterol trifenatate is cleared by CYP3A4 mediated extensive first-pass metabolism in the gastrointestinal tract and in the liver.
Coadministration with the strong CYP3A4 inhibitor ketoconazole (400 mg) increased mean vilanterol AUC_(0-t) and C_max, 65% and 22% respectively. The increase in vilanterol exposure was not associated with an increase in beta-agonist related systemic effects on heart rate, blood potassium or QT interval (corrected using the Fridericia method).
Care is advised when coadministering with strong CYP3A4 inhibitors (e.g. ketoconazole) as there is potential for an increased systemic exposure to vilanterol trifenatate, which could lead to an increase in the potential for adverse reactions (see Section 5.2 Pharmacokinetic Properties).

Interaction with P-glycoprotein inhibitors.

Both umeclidinium and vilanterol are substrates of P-glycoprotein (P-gp). The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium and vilanterol was assessed in healthy volunteers. No effect of verapamil was observed on umeclidinium or vilanterol C_max. An approximately 1.4-fold increase in umeclidinium AUC was observed with no effect on vilanterol AUC. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when umeclidinium bromide/ vilanterol is coadministered with P-gp inhibitors.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of umeclidinium/ vilanterol on human fertility. Studies in rats showed no effects of umeclidinium or vilanterol trifenatate on male and female fertility when the individual agents were administered at doses producing very large multiples of the systemic exposure in patients.
(Category B3)
There are no adequate and well controlled trials of umeclidinium/ vilanterol or its individual components, umeclidinium and vilanterol, in pregnant women. Teratogenicity has been observed in animals treated with vilanterol.
Embryofoetal development was unaffected by umeclidinium in rats treated at up to 278 micrograms/kilogram/day by inhalation (estimated to yield 50 times the plasma AUC in patients at the maximum recommended human dose of 62.5 micrograms per day) and in rabbits treated at up to 306 micrograms/kilogram/day by inhalation or up to 180 micrograms/kilogram/day subcutaneously (yielding 35 and ~ 200 times the plasma AUC in patients).
In rabbits, there was evidence of maternal toxicity and embryotoxicity following inhalation exposure to vilanterol 62.7 micrograms/kilogram/day, respectively (yielding at least 6 times the clinical exposure based on AUC). A nondose related increase in malformations, including the rare open eyelid, was also observed. In a separate study with subcutaneous exposure, increased incidence of open eye and increase in skeletal variations (indicative of developmental delay) occurred at 300 micrograms/kilogram/day (approximately 500 times the clinical exposure based on AUC) with a NOAEL of 30 micrograms/kilogram/day (equivalent to 36 times the clinical exposure based on AUC).
Anoro Ellipta should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the foetus.
It is unknown whether umeclidinium or vilanterol are excreted in human milk. However, other beta₂-agonists are detected in human milk. A risk to breastfed newborns/ infants cannot be excluded.
A decision must be made whether to discontinue breastfeeding or to discontinue Anoro 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

Ability to perform tasks that require judgement, motor or cognitive skills.

There have been no studies to investigate the effect of umeclidinium/ vilanterol on the ability to perform tasks that require judgement, motor or cognitive skills.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

6 month studies.

Table 1 shows all adverse events that occurred with a frequency of greater than 1% in groups receiving umeclidinium/ vilanterol 62.5/25 micrograms in the four 24 week well controlled studies (DB2113361, DB2113373, DB2113360 and DB2113374) where the rates in either of the groups receiving umeclidinium/ vilanterol 62.5/25 micrograms exceeded placebo by greater than 1%.

The safety data for study ZEP117115 are consistent with the safety data for the studies reported in Table 1.

12 month study.

In a long-term safety study (DB2113359), 335 subjects were treated for up to 12 months with umeclidinium/ vilanterol 125/25 micrograms or placebo. The demographic and baseline characteristics of the long-term safety study were similar to those of the placebo controlled efficacy studies. Adverse events that occurred with a frequency of greater than 1% in the group receiving umeclidinium/ vilanterol 125/25 micrograms and exceeded placebo by greater than 1% reported in this study were: back pain (umeclidinium/ vilanterol 4%, placebo 3%), cough (umeclidinium/ vilanterol 3%, placebo < 1%), urinary tract infection (umeclidinium/ vilanterol 2%, placebo 0%), abdominal pain (umeclidinium/ vilanterol 2%, placebo 0%), pleuritic pain (umeclidinium/ vilanterol 1%, placebo 0%), and diabetes mellitus (umeclidinium/ vilanterol 1%, placebo 0%).
The safety profile of umeclidinium/ vilanterol 62.5/25 micrograms is based on 2454 patients with COPD who received doses of umeclidinium/ vilanterol 62.5/25 micrograms or greater for up to one year during clinical studies. This includes 1124 patients who received umeclidinium/ vilanterol 62.5/25 micrograms and 1330 patients who received umeclidinium/ vilanterol 125/25 micrograms, both once daily.
Adverse drug reactions (ADRs) are listed in Table 2 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.

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

Symptoms and signs.

An overdose of Anoro Ellipta will likely produce signs and symptoms due to the individual components' actions, consistent with the known inhaled muscarinic antagonist adverse effects (e.g. dry mouth, visual accommodation disturbances and tachycardia) and those seen with overdose of other beta₂-agonists (e.g. tremor, headache 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 Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Anoro Ellipta is a combination inhaled long acting muscarinic receptor antagonist/ long acting beta₂-adrenergic agonist (LAMA/LABA). Following inhalation both compounds act locally on airways to produce bronchodilation by separate mechanisms.

Umeclidinium.

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.

Vilanterol.

Vilanterol is a selective long acting, beta₂-adrenergic receptor agonist (beta₂-agonist).
The pharmacologic effects of beta₂-agonists, including vilanterol, are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

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.
In one placebo controlled clinical efficacy study, umeclidinium/ vilanterol 62.5/25 micrograms increased FEV₁ after the first dose on day 1 with an improvement compared with placebo of 112 mL [95% CI = 96 mL to 129 mL] at 15 minutes following administration. The change from baseline to peak FEV₁ during 0-6 hours postdose at day 1 and week 24 was 273 mL and 320 mL respectively for umeclidinium/ vilanterol 62.5/25 micrograms compared with 106 mL (day 1) and 96 mL (week 24) for placebo. There was no evidence for tachyphylaxis to the bronchodilator effect after repeated dosing of umeclidinium/ vilanterol over time.

Cardiovascular effects.

The effect of umeclidinium/ vilanterol on the QT interval was evaluated in a placebo and moxifloxacin controlled QT study involving once daily administration of umeclidinium/ vilanterol 125/25 micrograms or 500/100 micrograms for 10 days in 103 healthy volunteers. The maximum mean difference in prolongations of QT interval (corrected using the Fridericia method, QTcF) from placebo after baseline correction was 4.3 (90% CI = 2.2 to 6.4) milliseconds seen 10 minutes after administration with umeclidinium/ vilanterol 125/25 micrograms and 8.2 (90% CI = 6.2 to 10.2) milliseconds seen 30 minutes after administration with umeclidinium/ vilanterol 500/100 micrograms. No clinically relevant effect on prolongation of QT interval (corrected using the Fridericia method) was observed.
In addition, no clinically significant effects of umeclidinium/ vilanterol on cardiac rhythm were observed on 24 hour Holter monitoring in 108 patients with COPD treated for up to 6 months (of whom 53 patients received umeclidinium/ vilanterol 62.5/25 micrograms and 55 patients received 125/25 micrograms once daily), and in a further 226 patients who received umeclidinium/ vilanterol 125/25 micrograms once daily for up to 12 months.

Clinical trials.

The safety and efficacy of umeclidinium/ vilanterol administered once daily were evaluated in eight phase III clinical studies in adult patients with a clinical diagnosis of COPD. Five studies were 6 month efficacy studies, two of these studies evaluated umeclidinium/ vilanterol 62.5/25 micrograms and umeclidinium/ vilanterol 125/25 micrograms (DB2113360 and DB2113374), two studies evaluated umeclidinium/ vilanterol 62.5/25 micrograms (DB2113373 and ZEP117115) and one study evaluated umeclidinium/ vilanterol 125/25 micrograms (DB2113361). In addition, there were two 12 week exercise endurance studies that included both umeclidinium/ vilanterol 62.5/25 micrograms and umeclidinium/ vilanterol 125/25 micrograms (DB2114417 and DB2114418) and one study (DB2113359) that evaluated the safety of umeclidinium/ vilanterol 125/25 micrograms administered over a 12 month treatment period. Efficacy results for umeclidinium/ vilanterol 62.5/25 micrograms are presented below.

Placebo controlled studies.

In the 6 month placebo controlled study (DB2113373) umeclidinium/ vilanterol 62.5/25 micrograms demonstrated a statistically significant improvement in lung function as defined by change from baseline trough FEV₁ (primary endpoint) compared with placebo. At week 24, umeclidinium/ vilanterol 62.5/25 micrograms increased trough FEV₁ by 167 mL (95% CI = 128 mL to 207 mL, p < 0.001) compared with placebo. Umeclidinium/ vilanterol 62.5/25 micrograms demonstrated greater improvements from baseline in weighted mean FEV₁ over 0-6 hours postdose at week 24 compared with placebo (242 mL [95% CI = 202 mL to 282 mL]). Bronchodilatory effects with umeclidinium/ vilanterol 62.5/25 micrograms compared with placebo were evident after the first day of treatment and were maintained over the 24 week treatment period.
Umeclidinium/ vilanterol 62.5/25 micrograms demonstrated clinically meaningful improvements compared with placebo in breathlessness (evaluated by TDI focal score), health related quality of life (as assessed by Saint George's Respiratory Questionnaire [SGRQ total score]) and rescue use throughout the study period (see Table 4).

Treatment with umeclidinium/ vilanterol 62.5/25 micrograms resulted in a lower risk of COPD exacerbation compared with placebo (analysis of time to first exacerbation: hazard ratio (HR) 0.5, 95% CI 0.3 to 0.8, risk reduction 50%).

Tiotropium comparator studies.

In two 6 month active controlled (tiotropium 18 micrograms administered once daily) studies (DB2113360 and ZEP117115), treatment with umeclidinium/ vilanterol 62.5/25 micrograms demonstrated statistically significant improvements in the primary endpoint of trough FEV₁ compared with tiotropium at week 24 in the first study (improvement over tiotropium by 90 mL [95% CI = 39 mL to 141 mL; p < 0.001]) and in the second and largest study (improvement over tiotropium by 112 mL [95% CI = 81 mL to 144 mL; p < 0.001]). In a third active controlled study DB2113374, treatment with umeclidinium/ vilanterol 62.5/25 micrograms showed a numerically greater improvement at week 24 compared with tiotropium (improvement over tiotropium by 60 mL [95% CI = 10 mL to 109 mL]).
In studies DB2113360 and ZEP117115, umeclidinium/ vilanterol 62.5/25 micrograms showed statistically significant greater improvements of 74 mL [95% CI = 22 mL to 125 mL; p = 0.005] and 105 mL [95% CI = 71 mL to 140 mL; p < 0.001] respectively in change from baseline in weighted mean FEV₁ over 0-6 hours at week 24 (secondary endpoint) compared with tiotropium. In study DB2113374, umeclidinium/ vilanterol 62.5/25 micrograms showed a clinically meaningful improvement of 96 mL [95% CI = 50 mL to 142 mL] in change from baseline in weighted mean FEV₁ over 0-6 hours at week 24 compared with tiotropium.
In studies DB2113360 and DB2113374, umeclidinium/ vilanterol 62.5/25 micrograms and tiotropium both improved measures of dyspnoea (TDI focal score) and health related quality of life (SGRQ) compared with baseline. In the third active comparator study (ZEP117115), a statistically significant improvement compared with tiotropium in the change from baseline SGRQ total score at week 24 was demonstrated for umeclidinium/ vilanterol (-2.10 units; p = 0.006). The percentage of patients receiving umeclidinium/ vilanterol that responded with a reduction from baseline of ≥ 4 units (MCID) in SGRQ total score from this study was 53% (237/445) compared with 46% (196/430) for tiotropium.
Statistically significant improvements in rescue salbutamol use over weeks 1-24 were observed for umeclidinium/ vilanterol 62.5/25 micrograms over tiotropium in studies DB2113360 (-0.7 puffs per day [95% CI = -1.2 to -0.1; p = 0.022]) and ZEP117115 (-0.5 puffs per day [95% CI = -0.7 to -0.2; p = < 0.001]).
Throughout studies DB2113360, ZEP117115 and DB2113374, patients treated with umeclidinium/ vilanterol had, on average, a greater reduction from baseline in the proportion of days when no rescue medication was needed (18.6%, 21.5% and 17.6% respectively) compared with tiotropium (11.7%, 13.3% and 13.4% respectively; no formal statistical analysis was performed on this endpoint).
In study ZEP117115, treatment with umeclidinium/ vilanterol 62.5/25 micrograms resulted in a lower risk of COPD exacerbation compared with tiotropium (analysis of time to first exacerbation: hazard ratio (HR), 0.5, 95% CI 0.3 to 1.0, risk reduction 50%, p = 0.044). These studies were not specifically designed to evaluate the effect of treatments on COPD exacerbations and patients were withdrawn from the study if an exacerbation occurred.

Supportive 3 month exercise endurance studies.

Exercise endurance was evaluated with the endurance shuttle walk test (ESWT) in adult COPD patients with hyperinflation (functional residual capacity [FRC] > 120%) in two replicate, 12 week clinical studies.
In the first study (DB2114418), treatment with umeclidinium/ vilanterol 62.5/25 micrograms demonstrated statistically significant improvement over placebo in exercise endurance time (EET) obtained 3 hours after dosing at week 12 of 69.4 seconds [95% CI = 24.5 seconds to 114.4 seconds; p = 0.003]. Improvement in EET compared with placebo was seen at day 2 and was sustained at week 6 and week 12. In the second study (DB2114417), treatment with umeclidinium/ vilanterol 62.5/25 micrograms did not show a statistically significant improvement in EET over placebo (21.9 seconds; p = 0.234).
In the first study, umeclidinium/ vilanterol 62.5/25 micrograms showed a statistically significant improvement compared to placebo in change from baseline in trough FEV₁ at week 12 of 243 mL [95% CI = 202 mL to 284 mL; p < 0.001] and a statistically significant improvement compared to placebo in change from baseline in lung volume measures at trough and at 3 hours postdose at week 12 (inspiratory capacity: 237 mL and 316 mL respectively, residual volume: -466 mL and -643 mL respectively and functional residual capacity: -351 mL and -522 mL respectively; all p < 0.001). In the second study, umeclidinium/ vilanterol 62.5/25 micrograms showed a clinically meaningful improvement compared to placebo in change from baseline in trough FEV₁ at week 12 of 211 mL [95% CI = 172 mL to 249 mL] and improvements compared to placebo in change from baseline in lung volume measures at trough and at 3 hours postdose at week 12 (inspiratory capacity: 198 mL and 238 mL respectively, residual volume: -295 mL and -351 mL respectively and functional residual capacity: -238 mL and -302 mL respectively).

5.2 Pharmacokinetic Properties

When umeclidinium and vilanterol were administered in combination by the inhaled route, the pharmacokinetics of each component was similar to those observed when each active substance was administered separately (see Section 5.2 Pharmacokinetic Properties, Metabolism; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). For pharmacokinetic purposes each component can therefore be considered separately.

Absorption.

Umeclidinium.

Following inhaled administration of umeclidinium in healthy volunteers, C_max 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.

Vilanterol.

Following inhaled administration of vilanterol in healthy volunteers, C_max occurred at 5 to 15 minutes. The absolute bioavailability of inhaled vilanterol was 27%, with negligible contribution from oral absorption. Following repeat dosing of inhaled vilanterol, steady state was achieved within 6 days with up to 2.4-fold accumulation.

Distribution.

Umeclidinium.

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%.

Vilanterol.

Following intravenous administration to healthy volunteers, the mean volume of distribution at steady state was 165 litres. In vitro plasma protein binding in human plasma was on average 94%.

Metabolism.

Umeclidinium.

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.

Vilanterol.

In vitro studies showed that vilanterol is metabolised principally via CYP3A4 and is a substrate for the P-gp transporter. The primary metabolic routes are O-dealkylation to a range of metabolites with significantly reduced beta₁ and beta₂-agonist activity. Plasma metabolic profiles following oral administration of vilanterol in a human radiolabel study were consistent with high first-pass metabolism. Systemic exposure to the metabolites is low.

Excretion.

Umeclidinium.

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.

Vilanterol.

Plasma clearance of vilanterol following intravenous administration was 108 litres/hour. Following oral administration of radiolabelled vilanterol, mass balance showed 70% of the radiolabel in urine and 30% in faeces. Primary elimination of vilanterol was by metabolism followed by excretion of metabolites in urine and faeces. Vilanterol plasma elimination half-life following inhaled dosing for 10 days averaged 11 hours.

Special patient populations.

Elderly.

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

Renal impairment.

Subjects with severe renal impairment showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (C_max and AUC), and no evidence of altered protein binding by umeclidinium or decreased protein binding by vilanterol between subjects with severe renal impairment and healthy volunteers was observed in vitro.

Hepatic impairment.

Subjects with moderate hepatic impairment showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (C_max and AUC), and no evidence of altered protein binding by umeclidinium or decreased protein binding by vilanterol between subjects with moderate hepatic impairment and healthy volunteers was observed in vitro. Umeclidinium/ vilanterol 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 or vilanterol 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.
Vilanterol was negative in assays for bacterial mutagenicity and transformation of Syrian hamster embryo cells in vitro, and for unscheduled DNA synthesis (hepatocytes) and the bone marrow micronucleus test in vivo in rats; the mouse lymphoma tk assay returned equivocal results. The weight of evidence suggests that vilanterol does not pose a genotoxic hazard.

Carcinogenicity.

No carcinogenicity studies have been performed with umeclidinium and vilanterol in combination.
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 to umeclidinium at the recommended dose of 62.5 micrograms per day in the respective species.
Consistent with findings for other beta₂-agonists, in 2 year inhalation studies vilanterol trifenatate caused proliferative effects in the female rat and mouse reproductive tract and in the rat pituitary gland. There was no increase in tumour incidence in rats or mice at doses producing AUC levels 0.5 or 13-fold the human clinical exposure of vilanterol at the maximum recommended dose of 25 micrograms per day in the respective species. These findings are not considered to indicate a carcinogenic hazard to patients.

6 Pharmaceutical Particulars

6.1 List of Excipients

Anoro 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 an 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

Anoro Ellipta (umeclidinium/ vilanterol 62.5/25 micrograms) is a moulded plastic inhaler with a light grey body, a red 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 two aluminium foil laminate strips 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

Umeclidinium bromide is slightly soluble in water and slightly soluble in methanol, ethanol, acetonitrile and propan-1-ol.
Vilanterol trifenatate is practically insoluble or insoluble in water and slightly soluble in methanol, ethanol, acetonitrile and propan-2-ol.

Chemical name.

The chemical name of umeclidinium bromide is 1-Azoniabicyclo[2.2.2]octane, 4- (hydroxydiphenylmethyl)-1-[2-(phenylmethoxy)ethyl]-, bromide (1:1).
The chemical name of vilanterol trifenatate is benzeneacetic acid, α,α-diphenyl-, compd. with (α1R)-α1-[[[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy] hexyl]amino]methyl]-4-hydroxy 1,3-benzene dimethanol (1:1).

Molecular formula.

Umeclidinium bromide: C₂₉H₃₄BrNO₂.
Vilanterol trifenatate: C₂₄H₃₃Cl₂NO₅.C₂₀H₁₆O₂.

Chemical structure.

Umeclidinium bromide.

Vilanterol trifenatate.

CAS number.

Umeclidinium bromide: 869113-09-7.
Vilanterol trifenatate: 503070-58-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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Anoro Ellipta

Umeclidinium; Vilanterol

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