Consumer medicine information

Alvesco

Ciclesonide

BRAND INFORMATION

Brand name

Alvesco

Active ingredient

Ciclesonide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alvesco.

What is in this leaflet

This leaflet answers some common questions about ALVESCO.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available. You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on this medicine.

Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits he/she expects it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What ALVESCO is used for

ALVESCO is inhaled into the lungs for the treatment of asthma. Asthma is a disease where the lining of the lungs becomes inflamed (red and swollen), making it difficult to breathe.

ALVESCO contains a medicine called ciclesonide, which belongs to a family of medicines called corticosteroids.

ALVESCO metered dose inhalers deliver a measured amount of ciclesonide, which acts directly on your air passages to reduce inflammation and help keep the air passages open. In doing so, this medication helps to improve your condition and to prevent asthma attacks from occurring. It is a preventer and needs to be taken regularly.

ALVESCO will NOT give you immediate relief of wheezing or breathlessness during sudden, severe or continuous asthma attacks. In this situation you should use a quick acting reliever inhaler, which contains a different medicine, a so-called bronchodilator.

Your doctor may prescribe ALVESCO to replace corticosteroid tablets, which will mean that you need to take both medicines for a short period of time. It is important to follow your doctor's instructions in using your medicines

Your doctor may have prescribed ALVESCO for another reason. Ask your doctor or pharmacist if you have any questions about why ALVESCO has been prescribed for you.

ALVESCO is not addictive.

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

Before you use ALVESCO

When you must not use it

Do not use ALVESCO if you have an allergy to:

  • any medicines containing ciclesonide
  • any of the ingredients listed at the end of this leaflet

Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Do not use ALVESCO to treat an acute asthma attack.

Do not give ALVESCO to a child under the age of 6 years.

Do not use ALVESCO after the expiry date (EXP) printed on the pack or if the packaging is damaged 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 using ALVESCO, contact your doctor.

Before you start to use it

Tell your doctor or pharmacist if you have any allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor if you are being treated for any fungal, bacterial or viral infections. Some treatments may interact with ALVESCO.

Tell your doctor if you are pregnant, intend to become pregnant. Like most medicines, ALVESCO is not recommended for use during pregnancy. If there is a need to consider ALVESCO during your pregnancy, your doctor will discuss the risks and benefits of using ALVESCO during pregnancy.

Tell your doctor if you are breastfeeding or plan to breastfeed. Your doctor will discuss the possible risks and benefits of using ALVESCO during breastfeeding.

Tell your doctor if you currently have an infection. If you take ALVESCO while you have an infection, the medication may hide some of the signs of an infection. This may make you think, mistakenly, that you are better or that it is not serious.

Tell your doctor if you have or have had tuberculosis (TB).

Tell your doctor if you have or are currently suffering from liver disease.

If you have not told your doctor about any of the above, tell them before you start using ALVESCO.

Using other medicines

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

Some medicines and ALVESCO may interfere with each other. These include:

  • medicines used to treat fungal or viral infections, such as ketoconazole, itraconazole, ritonavir, nelfinavir

These medicines may affect how well ALVESCO works.

How to use ALVESCO

If you are not sure how to use an inhaler, ask your doctor or pharmacist.

Children should only use their inhaler on medical advice and with the help of an adult.

The correct way to use your ALVESCO inhaler is explained on the instructions for use leaflet that comes inside the ALVESCO package. If you do not use your ALVESCO inhaler correctly your lungs might get less medicine than needed. So please read these instructions carefully before you start.

To make sure your ALVESCO inhaler delivers the correct dose you should clean it regularly as outlined in the instruction leaflet.

The doctor may have advised that you use a spacer device with your inhaler. This is also recommended for children 6-11 years of age.

If so, the AeroChamber Plus is considered a suitable device for use with ALVESCO.

When to use it

Use ALVESCO at the same time every day.

How much to use

Your doctor will have spoken to you about how much of your medicine you need to take. This will depend on your individual needs.

Your doctor will normally start you on 80 micrograms once daily if you are not currently using a preventer medication. Otherwise your starting dose will depend on your current medication and how well your asthma is controlled.

There are 2 strengths of ALVESCO and your doctor will have chosen the one which best suits your asthma. The number of puffs you are required to take daily will depend on the strength of ALVESCO you are using. Your doctor may adjust your dose so that you are taking the lowest dose of ALVESCO that will control your symptoms.

When your doctor is changing you from a corticosteroid tablet to ALVESCO, you will be asked to take both medicines for a period of time. Your dose of corticosteroid tablets will gradually be reduced to the lowest possible level. It is important you follow your doctor's instructions.

If you forget to use it

If you forget to use your ALVESCO inhaler, skip the dose you missed and use your next dose when you are meant to.

Do not use a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

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

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

How long to use it

ALVESCO helps control your asthma. Therefore, you must use ALVESCO every day. Continue using the medicine for as long as your doctor tells you.

Do not stop using it unless your doctor tells you to - even if you feel better.

If you use too much (overdose)

Do not use more than the recommended dose unless your doctor tells you to.

The risk of effects from taking too many puffs of ALVESCO is low.

If you are worried that you or anyone else may have used too much ALVESCO, telephone your doctor, or the Poisons Information Centre (telephone Australia 13 11 26).

While you are using ALVESCO

Things you must do

If you have an Asthma Action Plan that you have agreed with your doctor, follow it closely at all times.

Tell any other doctors, dentists and pharmacists who are treating you that you are using ALVESCO.

Tell your doctor or pharmacist that you are using ALVESCO if you are about to be started on any new medicines.

If you plan to have surgery (that needs a general anaesthetic), tell your doctor or dentist that you are using ALVESCO.

If you become pregnant while you are using ALVESCO, tell your doctor or pharmacist.

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

Things you must not do

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

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

Do not use ALVESCO to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop using ALVESCO, or lower the dosage, without checking with your doctor or pharmacist.

Things to be careful of

If ALVESCO does not have its usual effect
If your asthma gets worse tell your doctor. Your doctor may tell you to take extra puffs of ALVESCO or add another medicine (such as a reliever puffer) to your treatment.

If your breathing suddenly becomes more difficult just after you have used ALVESCO, you will need to use a reliever puffer and tell your doctor immediately.

Tell your doctor as soon as possible if:

  • your reliever puffer does not help your breathing as much as usual
  • the effect of your reliever puffer does not last as long as usual
  • you need more puffs of your reliever puffer than usual to get relief.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using ALVESCO.

All medicines can have unwanted side effects. Sometimes they are serious, but most of the time they are not. You may need medical attention if you get some of the side-effects.

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • nausea
  • bad taste in your mouth
  • mouth dryness
  • irritation in your mouth or throat
  • skin rash
  • high blood pressure
  • increased difficulty in breathing immediately following the use of ALVESCO

If you experience any of the following, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of the lips, mouth, tongue or throat
  • difficulty breathing
  • severe rash or welts on your skin

You may need urgent medical attention or hospitalisation.

Very rarely, inhaled corticosteroids may make you feel anxious, depressed, irritable, or have disturbed sleep.

It is possible that some people, particularly those taking higher doses of ALVESCO for a long time may rarely suffer from the following side effects:

  • rounded face
  • loss of bone density

Tell your doctor if you notice any issues with your eyes such as blurred vision or other problems with your eyesight. Your doctor may need to send you to an ophthalmologist (eye doctor) to check that you don't have eye problems such as cataracts (clouding of the eye lens), glaucoma (increased pressure in your eyeballs) or other rare eye conditions reported with corticosteroid use.

Children and adolescents who are receiving treatment for a long period of time may have their height checked regularly by their doctor. If your growth rate is slowed your doctor may adjust your treatment.

Your adrenal glands may be affected by taking high doses of corticosteroids over a long period of time or if you change from or use high doses of oral corticosteroids. Your doctor may need to check how the adrenal glands are working.

Your doctor may also tell you to take additional oral corticosteroids during periods when your body is stressed such as during trauma, surgery and infection.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using ALVESCO

Cleaning

Clean and dry your inhaler each time you use it. It is important to keep your inhaler clean and dry. It may not work as well if it gets dirty. Follow the instructions at the end of this leaflet for cleaning your inhaler.

Storage

Keep your inhaler in a cool, dry place where the temperature stays below 25°C.

Do not store ALVESCO or any other medicine in the bathroom, near a sink.

Do not leave it in the car on hot days or on a window sill. 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 using ALVESCO, or it has passed its expiry date, ask your pharmacist what to do with any that are left over.

Do not puncture or incinerate even when empty as the canister may explode.

Product description

What it looks like

The ALVESCO inhaler comprises an aluminium canister inside a plastic inhaler unit. The inhaler unit has a mouthpiece and a plastic cover.

ALVESCO comes in two different strengths - 80 micrograms and 160 micrograms.

ALVESCO 80 inhaler is registered* in 120 puffs.

ALVESCO 160 inhaler is registered* in 60 and 120 puffs.

*not all registered strengths and/or pack sizes might be available in Australia

Ingredients

ALVESCO contains ciclesonide as the active ingredient.

It also contains:

  • norflurane (a non-CFC propellant which does not deplete ozone from the atmosphere)
  • ethanol

ALVESCO does not contain gluten, sucrose, lactose, tartrazine or any other azo dyes.

Supplier

Emerge Health Pty Ltd
Suite 3, 22 Gillman Street,
Hawthorn East, VIC. 3123
T: +61 3 9077 4468
E: [email protected]

This leaflet was prepared on 1 April 2020

Australian Registration Number(s)

80 micrograms: AUST R 93724

160 micrograms: AUST R 93725

Instructions for Use

ALVESCO metered dose inhaler

Before using ALVESCO, please read these instructions carefully and follow them closely.

This leaflet does not contain all the available information. If you have any questions about ALVESCO, please refer to the Consumer Medicine Information on this leaflet. If this is a new inhaler or if you have not used your inhaler for one week or more, it must be tested before use by removing the mouthpiece cover and pressing down on the canister inside the inhaler. Release 3 puffs into the air, away from you.

You do not need to shake your inhaler before taking your medicine.

The medicine is already in a very fine solution, mixed to ensure you receive the correct dose with each puff.

Follow these instructions carefully and use the pictures to help you.

  1. Remove the mouthpiece cover and check inside and outside to make sure that the mouthpiece is clean and dry.

  1. Hold the inhaler upright with your forefinger on the top of the canister and your thumb on the base, below the mouthpiece.
  2. Breathe out as far as is comfortable.
  3. Place the mouthpiece in your mouth and close your lips firmly around it.
  4. Just after starting to breathe in through your mouth, press down on the top of the inhaler to release a puff while still breathing in slowly and deeply.

  1. Hold your breath, take the inhaler from your mouth and remove your finger from the top of the inhaler. Continue holding your breath for approximately ten seconds or as long as is comfortable.
  2. Breathe out slowly through your mouth.

  1. If you have been instructed to take another puff, wait about half a minute and repeat steps 3 to 7.
  2. After use, always replace the mouthpiece cover to keep out dust.

Replace firmly and snap into position.

It is important that you do not rush steps 3 to 7

A correct technique will ensure the right amount of ALVESCO is getting into your lungs every time you use your inhaler.

Care and Cleaning instructions

The mouthpiece of your inhaler should be cleaned weekly with a dry tissue or cloth.

DO NOT WASH OR PUT ANY PART OF THE ALVESCO INHALER IN WATER.

You should practice in front of the mirror for the first couple of times until you are confident that you are operating your inhaler properly. Make sure that none of your medicine is escaping from the top of inhaler or sides of your mouth.

If you find it difficult to use the inhaler with one hand, try using both hands. Put your two forefingers on top of the inhaler and both thumbs on the base below the mouthpiece. Tell your doctor, nurse or pharmacist if you are having difficulties.

When the canister is completely empty you will not feel or hear any of the propellant being discharged.

Use of inhaler with a spacer device

If your inhaler technique is poor, your doctor may recommend the use of a spacer device in combination with your inhaler. Different brands of spacers may affect the amount of medicine delivered to the lungs, so it is important that you be monitored for any loss of asthma control.

Before use, the spacer should be removed from the inhaler and washed in warm water and detergent and allowed to dry without rinsing or drying with a cloth. Wash the spacer at least monthly after use.

When using a spacer, you should inhale immediately after you press down on the top of the inhaler to release a puff.

Why would your Inhaler have stopped working?

Your inhaler may not work if:

  1. the mouthpiece is clogged and dirty
  2. the inhaler is empty (check by shaking the canister)
  3. the canister is wrongly positioned

If you have any questions about your ALVESCO medication, please refer to the Consumer Medicine Information.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Alvesco

Active ingredient

Ciclesonide

Schedule

S4

 

1 Name of Medicine

Ciclesonide.

2 Qualitative and Quantitative Composition

Alvesco is available in the following strengths:
Alvesco 80: 80 microgram ciclesonide per actuation;
Alvesco 160: 160 microgram ciclesonide per actuation.

Excipient(s) with known effect.

Ethanol.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Inhalation, pressurised.
The drug is dissolved in a non-halogenated solution and delivered via a pMDI, resulting in an extra fine aerosol. The main particle fraction ranges from 1.1 microns to 2.1 microns, which ensures high lung deposition (> 50% of the ex-actuator dose), and less deposition in the oropharynx than marketed suspension formulations of other ICS.

4 Clinical Particulars

4.1 Therapeutic Indications

Alvesco is indicated as prophylactic treatment of asthma in adults, adolescents and in children 6 years of age and older.

4.2 Dose and Method of Administration

Alvesco is for oral inhalation use only.
Symptoms start to improve with Alvesco within 24 hours of treatment. However, due to its prophylactic nature, Alvesco should be taken regularly even when patients are asymptomatic.

Dosing recommendation for children (6-11 years).

The recommended dose of Alvesco for children is 80 microgram or 160 microgram once daily. Alvesco can be administered as 1 or 2 puffs once daily either in the morning or evening. The use of a spacer is recommended for children 6-11 years (see Method of administration). The dose should be adjusted to the lowest dose at which effective control of asthma is maintained.

Dosing recommendation for adults and adolescents aged 12 years and older.

The recommended dose range is 80 to 320 microgram per day in adult and adolescent patients. In certain circumstances the dosage may be increased in adults (see Adult patients - higher doses in certain circumstances). Patients should be given a starting dose of Alvesco which is appropriate to the severity of their disease. Typical starting doses in patients either newly diagnosed or not previously treated with inhaled corticosteroids (ICS) are provided in Table 1.
Patients previously maintained on another ICS may require a higher dose depending on their current maintenance dose. Alvesco can be administered as 1 or 2 puffs once daily either in the morning or evening. In the case of a higher dose, twice daily administration is recommended (see Adult patients - higher doses in certain circumstances). The dose should be adjusted to the lowest dose at which effective control of asthma is maintained.

Adult patients - higher doses in certain circumstances.

Adults with severe asthma may have their daily dose increased from 320 microgram once daily to 320 microgram twice daily. However, the superiority of this higher dose versus 320 microgram once daily has not been unequivocally established (see Section 5.1, Clinical trials; Section 4.4). The dose should be adjusted to the lowest dose at which effective control of asthma is maintained.
When transferring a patient from an oral steroid to ciclesonide, the patient should be in a relatively stable phase. A high dose of ciclesonide should be given in combination with the oral steroid for about 10 days. The oral steroid should be gradually reduced to the lowest possible level.

Special patient populations.

Renal impairment.

There is no need to adjust the dose in patients with renal impairment.

Hepatic impairment.

There is no need to adjust the dose in patients with hepatic impairment.
Systemic exposure to the active metabolite (M1; 21-des-isobutyryl-ciclesonide) is increased in patients with hepatic impairment (see Section 5.2).

Use in the elderly.

There is no need to adjust the dose in elderly patients.

Use in paediatric patients.

To date, there is insufficient data available in the treatment of children of 5 years and younger with Alvesco.

Method of administration.

For detailed instructions see the Patient Instruction Leaflet.
The mouthpiece should be cleaned with a dry tissue or cloth weekly, do not wash the inhaler or put any part of the inhaler in water.
Because of the already high lung deposition and low deposition of active corticosteroid in the oropharynx, the use of a spacer with Alvesco is not routinely recommended for all patients. However, some patients may benefit from the consistent use of a spacer device in conjunction with their metered dose inhaler, particularly those with poor inhaler technique and children (6-11 years) as mentioned above. If a spacer is considered necessary, the AeroChamber Plus is a suitable device for using with Alvesco. The patient should be instructed to inhale after each actuation of drug into the spacer. Any delay between actuation and inhalation should be kept to a minimum.
Electrostatic charge on the walls of the spacer may cause variability in drug delivery. Patients should be instructed to wash the spacer in warm water and detergent and allow it to dry without rinsing or drying with a cloth. This should be performed before initial use of the spacer and at least monthly thereafter. In those patients using a spacer, a change in the make of spacer may be associated with an alteration in the amount of drug delivered to the lungs. The clinical significance of such alterations is uncertain. However, in these situations, the patient should be monitored for any loss of asthma control.

4.3 Contraindications

Alvesco should not be used in case of known hypersensitivity to any of the ingredients.

4.4 Special Warnings and Precautions for Use

As with all ICS, Alvesco should be administered with caution in patients with active or quiescent pulmonary tuberculosis, fungal, bacterial or viral infections, and only if these patients are adequately treated.
As with all ICS, Alvesco is not indicated in the treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
As with all ICS, Alvesco is not designed to relieve acute asthma symptoms for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.
Patients with severe asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests. Increasing use of short acting bronchodilators to relieve asthma symptoms indicate deterioration of asthma control. If patients find that short acting relief bronchodilator treatment becomes less effective, or they need more inhalations than usual, medical attention must be sought. In this situation, patients should be reassessed and consideration given to the need for increased anti-inflammatory treatment therapy (e.g. higher doses of ICS or a course of oral corticosteroids). The maximal daily dose is 640 microgram/day (given as 320 microgram twice a day but the superiority of this dose over 320 microgram/day has not been unequivocally demonstrated (see Section 5.1, Clinical trials). Severe asthma exacerbations should be managed according to standard medical practice.

Systemic effects.

Inhaled steroid products are designed to direct glucocorticoid delivery to the lungs in order to reduce overall systemic glucocorticoid exposure and side effects. In sufficient doses however, all ICS can have adverse effects, notably depression of the hypothalamic pituitary adrenal (HPA) axis, reduction of bone density, cataract, glaucoma and retardation of growth rate in children and adolescents. In steroid dependent patients, prior systemic steroid usage may be a contributing factor, but such effect can occur amongst patients who use only ICS regularly.

HPA axis suppression and adrenal insufficiency.

The lowest dose of ciclesonide that causes suppression of the HPA axis (as indicated by 24-hour urinary cortisol concentrations), effects on bone mineral density or growth retardation in patients has not yet been established.
A controlled study compared 24-hour plasma cortisol AUC in 26 adult asthmatic patients following 7 days of treatment. Compared to placebo, treatment with ciclesonide 320, 640 and 1280 microgram/day did not statistically lower the 24-hour time averages of plasma cortisol (AUC(0-24)/24 hours) nor was a dose dependent effect seen. Hence, at therapeutic doses, no significant difference was detected between inhaled ciclesonide and placebo on HPA function and serum cortisol levels. However, potential effects on the HPA axis may occur in individual patients particularly at times of physiological stress (e.g. hot climate, illness or surgery). Similar results were seen in other studies in asthmatic children aged 4 to 12 years.

Growth.

It is recommended that the height of children and adolescents receiving prolonged treatment with ICS is regularly monitored. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Visual disturbance.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Transfer from oral corticosteroids.

The benefits of inhaled ciclesonide should minimise the need for oral corticosteroids. However, patients transferred from oral steroids may remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled ciclesonide. The possibility of adverse effects may persist for some time. These patients may require specialised advice to determine the extent of adrenal impairment before elective procedures. The possibility of residual impaired adrenal response should always be considered in emergency (medical or surgical) and elective situations likely to produce stress, and appropriate corticosteroid treatment considered. Transfer of patients from systemic corticosteroid therapy to Alvesco may unmask pre-existing allergic conditions such as allergic rhinitis or eczema, previously suppressed by systemic corticosteroid therapy.

General.

Paradoxical bronchospasm with an immediate increase of wheezing or other symptoms of bronchoconstriction after dosing should be treated with an inhaled short-acting bronchodilator which usually results in quick relief. If the patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual, medical attention must be sought. This indicates a worsening of the underlying conditions, and warrants a reassessment of the therapy.
The patient should be assessed and therapy with Alvesco should only be continued if, after careful consideration, the expected benefit is greater than the possible risk. Correlation between severity of asthma and general susceptibility for acute bronchial reactions should be kept in mind (see Section 4.8).
The patient should be advised against abrupt discontinuation of therapy with Alvesco.
Patient inhaler technique should be checked regularly to make sure that inhaler actuation is synchronised with inhalation to ensure optimum delivery to the lungs (see Section 4.2).
Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should be avoided unless the benefit outweighs the increased risk of systemic side effects of corticosteroids (see Section 4.5).

Use in hepatic impairment.

Systemic exposure to the active metabolite (M1) is increased in patients with hepatic impairment (see Section 5.2, Pharmacokinetic characteristics in special patient populations, Hepatic impairment). Although no dosage reduction is necessary, prescribers should be aware of the possibility of an increased risk of systemic adverse effects (see Section 4.2, Hepatic impairment).

Use in the elderly.

Systemic exposure to M1 is also increased in elderly patients (see Section 5.2, Pharmacokinetic characteristics in special patient populations, Use in the elderly). Although no dosage reduction is necessary, prescribers should be aware of the possibility of an increased risk of systemic adverse effects in such patients (see Section 4.2, Use in the elderly).

Paediatric use.

See Section 5.1, Clinical trials.
To date, there is insufficient data available in the treatment of children of 5 years and younger with Alvesco.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In a drug-drug interaction study at steady state with ciclesonide and ketoconazole as a potent CYP3A4 inhibitor, the exposure to the active metabolite M1 increased approximately 3.5-fold, whereas the exposure to ciclesonide was not affected. Therefore, the concomitant administration of potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole and ritonavir or nelfinavir) should be avoided unless the benefit outweighs the increased risk of systemic side effects of corticosteroids.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility was not affected in rats given 900 microgram/kg/day ciclesonide given by oral gavage.
(Category B3)
There are no adequate and well controlled studies in pregnant women.
In animal studies glucocorticoids have been shown to induce malformations. Corticosteroids are known to induce foetotoxic and teratogenic effects in rodent and rabbit studies.
Embryofoetal development studies with daily SC dosing of ciclesonide in rabbits, abnormal foetal development (cleft palate, hind paw flexure, enlarged fontanelle, parchment like skin) was observed at systemic exposure levels (based on plasma AUC) ranging from about 3 to 12 times that anticipated clinically at the maximum recommended human dose.
Embryofoetal development studies in rats showed reduced foetal weight, skeletal anomalies, hydronephrosis and maternotoxicity at oral doses of 300-900 microgram/kg/day.
Similar studies with these doses extended until weaning revealed maternotoxicity, reduced pup weight gain, changes in pup organ weight and changes in behavioural development tests. The systemic exposure of dams relative to human exposure in these studies is not known, but doses represented 2-6 times the maximum recommended human dose on a body surface area basis.
As with other ICS preparations, Alvesco is not to be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the mother or foetus. The lowest effective dose of ciclesonide needed to maintain adequate asthma control should be used. Infants born of mothers who received corticosteroids during pregnancy are to be observed carefully for hypoadrenalism.
The excretion of ciclesonide or its metabolites into human milk has not been investigated.
There was limited excretion of ciclesonide and/or its metabolites into milk in lactating rats after intravenous or oral administration (respective maxima of 0.23% and 0.03% of dose/g tissues). Oral administration of ciclesonide to rats from early pregnancy until weaning was associated with adverse effects on dams and pups (see Use in pregnancy above in this section).
In breastfeeding mothers, the therapeutic benefits of the drug should be weighed against the potential hazards to mother and baby.

4.7 Effects on Ability to Drive and Use Machines

Alvesco has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data in adults and adolescents.

Approximately 5% of patients experienced adverse reactions in clinical trials with Alvesco given in the dose range 80 to 1280 microgram per day. In the majority of cases, these were mild and did not require discontinuation of treatment with Alvesco.
Table 2 shows the adverse events reported with a frequency of ≥ 2% from participants in studies of up to 1-year duration.
The following adverse reactions have also been reported in clinical trials with Alvesco. (See Table 3.)
Paradoxical bronchospasm may occur immediately after dosing and is an unspecific acute reaction to all inhaled medications, which may be related to the drug, the excipient or evaporation cooling in the case of metered dose inhalers. In the majority of cases, this reaction is mild and does not require withdrawal of Alvesco. In severe cases, withdrawal of Alvesco should be considered.

Clinical trial data in children.

In children, the overall frequency of treatment emergent adverse events seen with Alvesco treatment was lower than that seen with placebo treatment. There was no evidence of any negative effect of Alvesco on short or long-term growth velocity.
The following adverse reactions were recorded during clinical trials in children (N=2827) with Alvesco, regardless of causality. (See Table 4.)

Post marketing experience.

Very rare cases of immediate or delayed hypersensitivity reactions such as angioedema with swelling of lips, tongue and pharynx have been reported from spontaneous reporting with Alvesco.
There have been very rare reports of psychiatric symptoms such as agitation, insomnia, depression, anxiety and behavioural changes with ciclesonide as well as with other ICS.
Systemic effects of ICS may occur, particularly at doses higher than recommended. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents and decrease in bone mineral density (see Section 4.4, Systemic effects).
Eye disorders with frequency unknown, such as blurred vision, cataract or glaucoma, have been reported with systemic and topical corticosteroid use (see Section 4.4, Systemic effects).

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

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

Acute.

Inhalation by healthy volunteers of a single dose of 2880 microgram of ciclesonide was well tolerated. The potential for acute toxic effects following overdose of inhaled Alvesco is low. After acute overdosage no specific treatment is necessary.

Chronic.

After prolonged administration of 1280 microgram of ciclesonide no significant clinical signs of adrenal suppression were observed. However, if higher than recommended dosage is continued over prolonged periods, some degree of adrenal suppression cannot be excluded. Monitoring of adrenal reserve may be necessary. In cases of ciclesonide overdose, therapy may still be continued at a suitable dosage for symptom control.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ciclesonide (pure R-epimer) belongs to a new class of on-site activated non-halogenated ICS. Ciclesonide is an ester pro-drug with approximately 100-fold lower affinity for the glucocorticoid receptor than its active metabolite (M1; 21-des-isobutyryl-ciclesonide) and budesonide and fluticasone. Endogenous activation occurs primarily via esterases located in the lung, to give M1.
Bronchial inflammation is known to be an important component in the pathogenesis of asthma. Inflammation occurs in both large and small airways and also causes an associated increase in airway responsiveness to a variety of inhaled stimuli. In clinical trials, ciclesonide has been shown to reduce airway reactivity to adenosine monophosphate in hyperreactive patients. Pre-treatment with ciclesonide for seven days significantly attenuated the early and late phase reactions following inhaled allergen challenge. Inhaled ciclesonide treatment was also shown to attenuate the increase in inflammatory cells (total eosinophils) and inflammatory mediators in induced sputum.

Clinical trials.

Clinical trials in adults and adolescents.

Forty-two studies with Alvesco pMDI were initiated in Europe, Canada, Japan, USA and South Africa. Over 14,000 patients were evaluated including adolescents (12-17 years), adults and elderly patients (65-75 years). Most studies were double blind, some were placebo controlled whereas others used beclomethasone dipropionate, budesonide or fluticasone propionate as an active control. Patients classified as mild, moderate or severe asthmatics were included.
Alvesco was demonstrated to be well tolerated and effective in treating asthma of varying disease severity in adults and adolescents. Safety and efficacy was maintained over 12 months.
Treatment with Alvesco in recommended doses did not cause HPA axis suppression as measured by 24-hour serum and urine cortisol concentrations or cosyntropin tests.
Tables 5, 6 and 7 present the outcome of primary endpoints in efficacy studies comparing Alvesco with placebo, budesonide and fluticasone propionate. All studies were a randomised (evenly) parallel group design of 12 weeks duration.

Dose finding studies to support 640 microgram/day.

In the original registration data set, efficacy studies did not find a dose effect between ciclesonide 160 microgram/day and 640 microgram/day doses (FK1 102) or between ciclesonide 80 microgram/day and 320 microgram/day doses (FK1 101) in patients with mild to moderate asthma. Lack of efficacy was present in 66 out of 110 placebo group patients in FK1 102 compared with 31 out of 107 patients on 160 microgram/day and 32 out of 112 patients on 640 microgram/day ciclesonide. FK1 104 did not show superiority (PEFR or FEV1) of 1,280 microgram/day ciclesonide/day over 640 microgram/day in patients with severe asthma. Study FK1 104 did not use a comparator dose of ciclesonide 320 microgram/day. It does not provide evidence to support a dose exceeding 640 microgram/day. Study 193/2000 compared ciclesonide 80 or 320 microgram/day with budesonide 400 microgram/day; both doses were non-inferior.
Late studies that examined dose-response of ciclesonide over 320 microgram/day were studies M1 140 (ciclesonide 160 microgram/day versus 640 microgram/day) and XRP 323/324 (640 and 320 microgram/day and fluticasone propionate 880 microgram/day).

Study M1 140.

The objective of this randomised, parallel group study (n = 680 patients) was to show superiority of ciclesonide 320 microgram twice a day over ciclesonide 160 microgram/day. There were two primary variables over the 12-week treatment phase: time to first asthma exacerbation (loss of efficacy) and change in FEV1 from T0 to Tend/last. First asthma exacerbation/ loss of efficacy was defined as worsening asthma which required treatment with additional asthma medications other than increased use of rescue medication. After a 2-week baseline period when the patients received fluticasone propionate 250 microgram twice a day, randomization occurred if FEV1 were ≤ 70% predicted, asthma symptom scores ≥ 4 for the 4 of the last 7 days before randomization or ≥ puffs of rescue medication were used in the last 4 days before randomization. Six hundred and eighty patients were randomised to (ratio 1:1):341 to ciclesonide 640 microgram/day and 339 to ciclesonide 160 microgram/day; 595 of them completed the study (ciclesonide 640 microgram/day 91.2% and ciclesonide 160 microgram/day 71.1%). Ciclesonide 640 microgram/day (320 microgram twice daily) was superior to ciclesonide 160 microgram/day with regard to time to occurrence of a first exacerbation (p = 0.005) 12.7% of patients in the ciclesonide 160 microgram/day group and 6.7% of patients in the ciclesonide 640 microgram/day experienced exacerbation. For the second primary efficacy variable, FEV1 (L/min) from T0 to Tend/last, this increased in both treatment groups; ciclesonide 160 microgram/day 0.269 and ciclesonide 320 microgram twice a day 0.332 (both p < 0.0001) but superiority of ciclesonide 320 microgram twice a day over ciclesonide 160 microgram/day was not shown.
Ciclesonide 320 microgram twice a day - ciclesonide 160 microgram/day Δ 0.062 (p = 0.0639). This study did not use a comparator dose of ciclesonide 320 microgram/day. The added benefit of 320 microgram twice a day over 320 microgram/day was not examined.

Study XRP 323/324.

Was a phase III double-blind, double dummy, parallel-group, multicentre, placebo-controlled, efficacy and safety study of ciclesonide pMDI 320 microgram/day, 640 microgram/day and Flovent pMDI (fluticasone propionate) 880 microgram/day (ex-actuator) administered twice daily for 12 weeks in the treatment of severe persistent asthma in adolescents and adults. Patients were required to have been on ≥ 500 microgram fluticasone propionate or equivalent for at least one month prior to baseline and used β2-agonist > twice per week. During baseline the patients took 50 or 25% of their usual ICS dose. At randomization, FEV1 was ≥ 40% and ≤ 65% predicted and a reduction of ≥ 10% from the actual FEV1 value at entry to baseline. The primary efficacy variable was change in FEV1 from baseline to week 12 and the primary efficacy analysis was the treatment difference between active treatments and placebo. The first comparison was between ciclesonide 640 microgram/day and placebo followed by the comparison between ciclesonide 320 microgram/day and placebo. The intent to treat population totalled 527 patients. FEV1, improved significantly from T0 to T12 for all treatments: 0.25 L/min for placebo, 0.36 L/min for ciclesonide 320 microgram, 0.43 L/min for ciclesonide 640 microgram, and 0.50 L/min for FP 880 microgram. There was a statistically significant difference in FEV1 for ciclesonide 640 microgram vs. placebo, (Δ 0.18, p = 0.0008), ciclesonide 320 microgram/day vs. placebo (Δ 0.11, p = 0.0374) and fluticasone 880 vs. placebo (0.24, p = 0.0001)). The treatment differences between ciclesonide 640 microgram and 320 microgram and ciclesonide 640 microgram and fluticasone 880 microgram treatment groups were not significant clinically or statistically but some dose-related trends were seen.

Study FK1 102.

Was a placebo controlled, parallel group study that compared 12 weeks treatment with 160 or 640 microgram/day ciclesonide or placebo; the primary efficacy variables were change in morning peak expiratory flow from initial to last observation and the fraction of patients with predefined loss of efficacy up to week 12. The adults enrolled had mild to moderate asthma. This was a superiority study of ciclesonide 640 microgram/day and then ciclesonide 160 microgram/day compared to placebo. The first comparison did not show superiority.

Note.

This study did not use a comparator dose of ciclesonide 320 microgram/day. Added benefit of 640 microgram/day over ciclesonide 160 microgram/day was not shown in mild to moderate asthma.

Clinical trials in children (under 12 years of age).

In four active-controlled studies of 12 weeks duration in children comparable efficacy to the respective active control was shown for lung function as measured by FEV1 and peak expiratory flow, asthma symptom scores, and need for inhaled β2-agonist. In two of these studies ciclesonide was administered with a spacer.
The effect on growth in 609 children aged 5 to 9 years was investigated in a placebo-controlled multi-centre, double-blind, randomised parallel-group study of 12 months duration. In the modified intention-to-treat (mITT) analysis, the mean growth velocities observed during the double-blind treatment period were 5.76 cm/year in the placebo group, 5.75 cm/year in the 40 microgram ciclesonide group, and 5.60 cm/year in the 160 microgram ciclesonide group. It can be concluded that doses of ciclesonide administered at 40 microgram or 160 microgram once daily were noninferior to placebo with respect to growth velocity. In addition, no significant difference was observed between ciclesonide and placebo as measured by 24-hour urinary free cortisol in 292 patients who were studied for HPA axis function.
Growth was also assessed by stadiometry in one of the double-blind, double-dummy, randomised parallel group 12-week studies in a subset of patients (ciclesonide 160 microgram od with spacer: N = 58, budesonide 400 microgram od administered by DPI: N = 26). Height increased by 1.2 cm in the ciclesonide group and by 0.7 cm in the budesonide group. A between treatment comparison showed superiority of ciclesonide over treatment with budesonide (p = 0.0025).

5.2 Pharmacokinetic Properties

Ciclesonide is dissolved in a non-halogenated solution which results in a finer aerosol and less oropharyngeal deposition than suspension formulations of other ICS. In addition, ciclesonide is delivered as a pro-drug, with a low level of conversion to the active metabolite (M1) in the oropharynx.
In the following all doses of Alvesco are given as ex-actuator. 160 microgram Alvesco ex-actuator corresponds to 200 microgram ex-valve. Doses for other ICS are given as ex-valve.
In a study comparing oropharyngeal deposition, the AUC (in nanomol x hr/L) of M1 recovered from the oropharynx after a 640 microgram dose of Alvesco was 4% of the AUC of budesonide recovered after an 800 microgram (ex-valve) dose of a suspension formulation of budesonide.
Similarly, the AUC of M1 recovered from the oropharynx after a 640 microgram dose of Alvesco was 8% of the AUC of fluticasone recovered after a 1000 microgram dose (ex-valve) of a suspension formulation of fluticasone.
Based upon a γ-scintigraphy experiment in healthy subjects, 52% of the dose leaving the Alvesco pMDI is deposited in the lungs. In line with this figure, the mean systemic bioavailability for M1 is ≥ 50%. Systemic exposure to M1 is approximately proportional to dose.
Studies with oral and intravenous dosing of radiolabelled drug have shown an incomplete extent of oral absorption (24.5%). With a powder capsule formulation of ciclesonide, the oral bioavailability of both ciclesonide and M1 is low (< 0.5% for ciclesonide, < 1% for M1). The swallowed portion of the inhaled drug is not expected to contribute significantly to systemic absorption.

Distribution.

Following IV administration of ciclesonide the volume of distribution was estimated at 2.9 L/kg for ciclesonide and 12.1 L/kg for M1. Ciclesonide and M1 are highly bound to plasma proteins (98-99%).

Metabolism.

Ciclesonide is primarily hydrolysed to M1 by esterase enzymes in the lung. Studies with human liver microsomes showed that M1 is metabolised predominantly by CYP3A4 catalysis to hydroxylated metabolites, which have a lower affinity (4-15 fold) than M1 for the glucocorticosteroid receptor. Furthermore, in studies in rats, lipophilic fatty acid ester conjugates of the M1 in the lung were detected. This could maintain levels of the active principle due to C21-ester hydrolysis in the lung.

Excretion.

Following IV administration of ciclesonide, clearance of ciclesonide was 152 L/hr and clearance of M1 was estimated at 228 L/hr. Half-life was estimated at 0.94 hours for ciclesonide and 2.8 hours for M1.
Ciclesonide and its metabolites are predominantly excreted via the faeces, after oral and intravenous administration, indicating that biliary excretion is the major route of elimination.

Pharmacokinetic characteristics in special patient populations.

Hepatic impairment.

Following a single inhaled dose of 1280 microgram of Alvesco in patients with moderate or severe cirrhosis, plasma concentrations of M1 were increased approximately two-fold compared to healthy subjects.

Use in the elderly.

Following a single inhaled dose of 1280 microgram of Alvesco in healthy elderly male subjects, plasma concentrations of M1 were increased approximately two-fold compared to healthy young male subjects.

5.3 Preclinical Safety Data

Genotoxicity.

Ciclesonide did not induce gene mutations in bacterial or mammalian assays in vitro, nor induce chromosomal aberrations in CHO cells or human lymphocytes in vitro. However, ciclesonide induced micronuclei in mouse bone marrow in vivo in oral doses ≥ 75 mg/kg in females and > 1000 mg/kg in males. The estimated systemic exposure (plasma AUC) to the active metabolite at the no effect dose level was ≥ 6 times that expected in humans at the maximum clinical dose. Positive in vivo clastogenicity results have also been observed with other corticosteroids and may result from effects on erythrocyte differentiation. The clinical relevance of these clastogenicity findings is unknown.

Carcinogenicity.

Carcinogenicity was investigated in a 2-year inhalation study in rats receiving up to 104 microgram/kg/day (females) or 90 microgram/kg/day (males) ciclesonide and in a 2-year oral study in mice receiving up to 900 microgram/kg/day ciclesonide respectively.
Gastric adenomas (benign tumour) were significantly increased in female mice receiving a 70-fold higher dose (on a mg/kg basis) compared to the amount of the maximal recommended clinical inhalation dose estimated to be swallowed per day. This effect may arise from a local action in the antrum.
There were no significant tumorigenic effects of low doses of ciclesonide in the rat 2 year inhalation study (systemic exposure based on plasma AUC that is similar to that expected in humans given the maximum daily dose).

6 Pharmaceutical Particulars

6.1 List of Excipients

Ethanol and norflurane ((HFA-134a) a propellant, which does not contain chlorofluorocarbons (CFCs)).

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 25°C. Do not refrigerate or freeze. Do not puncture or incinerate even when empty as canister may explode.

6.5 Nature and Contents of Container

Alvesco is registered* in the following pack sizes.

Alvesco 80.

60 or 120 inhalations.

Alvesco 160.

60 or 120 inhalations.
*Not all presentations may be available 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: [11β,16α (R)]-16,17-[(Cyclohexylmethylene)bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy) pregna-1,4-diene-3,20-dione.

Chemical structure.


CAS number.

126544-47-76.
Molecular formula: C32H44O7.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes