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ALVESCO 80 INHALER

Active substance: CICLESONIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Alvesco® 80 Inhaler

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 actuation (delivered dose from the mouthpiece) contains 80 micrograms of
ciclesonide.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Pressurised inhalation, solution
Clear and colourless

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment to control persistent asthma in adults and adolescents (12 years and
older).

4.2

Posology and method of administration
The medicinal product is for inhalation use only.
Dosing recommendation for adults and adolescents:
The recommended dose of Alvesco® is 160 micrograms once daily, which
leads to asthma control in the majority of patients. However in severe
asthmatics, a 12 week study has shown that a dose of 640 micrograms/day
(given 320 micrograms twice daily) has demonstrated a reduction in the
frequency of exacerbations but without an improvement in lung function (see
section 5.1). Dose reduction to 80 micrograms once daily may be an effective
maintenance dose for some patients.

Alvesco® should preferably be administered in the evening although morning
dosing of Alvesco® has also been shown to be effective. The final decision on
evening or morning dosing should be left to the discretion of the physician.
Symptoms start to improve with Alvesco® within 24 hours of treatment. Once
control is achieved, the dose of Alvesco® should be individualised and titrated
to the minimum dose needed to maintain good asthma control.
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
indicates 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. a higher dose of Alvesco for a short
period [see section 5.1] or a course of oral corticosteroids). Severe asthma
exacerbations should be managed the usual way.
To address specific patient needs, such as finding it difficult to press the
inhaler and breathe in at the same time, Alvesco® can be used with the
AeroChamber PlusTM spacer device.
Specific patient groups:
There is no need to adjust the dose in elderly patients or those with hepatic or
renal impairment.
To date, there are insufficient data available in the treatment of children under
12 years of age with ciclesonide.
Instructions for use / handling:
The patient needs to be instructed how to use the inhaler correctly.
If the inhaler is new or has not been used for one week or more, three puffs
should be released into the air. No shaking is necessary as this is a solution
aerosol.
During inhalation, the patient should preferably sit or stand, and the inhaler
should be held upright with the thumb on the base, below the mouthpiece.
Instruct the patient to remove the mouthpiece cover, place the inhaler into their
mouth, close their lips around the mouthpiece, and breathe in slowly and
deeply. While breathing in through the mouth, the top of the inhaler should be
pressed down. Then, patients should remove the inhaler from their mouth, and

hold their breath for about 10 seconds, or as long as is comfortable. The
patient is not to breathe out into the inhaler. Finally, patients should breathe
out slowly and replace the mouthpiece cover.
The mouthpiece should be cleaned with a dry tissue or cloth weekly. The
inhaler should not be washed or put in water.
For detailed instructions see Patient Information Leaflet.

4.3

Contraindications
Hypersensitivity to ciclesonide or any of the excipients.

4.4

Special warnings and precautions for use

As with all inhaled corticosteroids, Alvesco should be administered with caution in
patients with active or quiescent pulmonary tuberculosis, fungal, viral or bacterial
infections, and only if these patients are adequately treated.
As with all inhaled corticosteroids, Alvesco is not indicated in the treatment of status
asthmaticus or other acute episodes of asthma where intensive measures are required.
As with all inhaled corticosteroids, 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.
Systemic effects of inhaled corticosteroids may occur, particularly at high doses
prescribed for prolonged periods. These effects are much less likely to occur than with
oral corticosteroids. Possible systemic effects include adrenal suppression, growth
retardation in children and adolescents, decrease in bone mineral density, cataract and
glaucoma, and more rarely, a range of psychological or behavioural effects including
psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression
(particularly in children). It is therefore important that the dose of inhaled
corticosteroid is titrated to the lowest dose at which effective control of asthma is
maintained.
It is recommended that the height of children and adolescents receiving prolonged
treatment with inhaled corticosteroids is regularly monitored. If growth is slowed,
therapy should be reviewed with the aim of reducing the dose of inhaled
corticosteroid, if possible to the lowest dose at which effective control of asthma is
maintained. In addition, consideration should be given to referring the patient to a
paediatric respiratory specialist.
There is no data available in patients with severe hepatic impairment. An increased
exposure in patients with severe hepatic impairment is expected and these patients
should therefore be monitored for potential systemic effects.

The benefits of inhaled ciclesonide should minimise the need for oral steroids.
However, patients transferred from oral steroids remain at risk of impaired adrenal
reserve for a considerable time after transferring to inhaled ciclesonide. The
possibility of respective symptoms 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 an emergency (medical or surgical) and
elective situations likely to produce stress, and appropriate corticosteroid treatment
considered.
For the transfer of patients being treated with oral corticosteroids:
The transfer of oral steroid-dependent patients to inhaled ciclesonide, and their
subsequent management, needs special care as recovery from impaired adrenocortical
function, caused by prolonged systemic steroid therapy, may take a considerable time.
Patients who have been treated with systemic steroids for long periods of time, or at a
high dose, may have adrenocortical suppression. With these patients adrenocortical
function should be monitored regularly and their dose of systemic steroid reduced
cautiously.
After approximately a week, gradual withdrawal of the systemic steroid is started by
reducing the dose by 1 mg prednisolone per week, or its equivalent. For maintenance
doses of prednisolone in excess of 10 mg daily, it may be appropriate to cautiously
use larger reductions in dose at weekly intervals.
Some patients feel unwell in a non-specific way during the withdrawal phase despite
maintenance or even improvement of respiratory function. They should be encouraged
to persevere with inhaled ciclesonide and to continue withdrawal of systemic steroid,
unless there are objective signs of adrenal insufficiency.
Patients transferred from oral steroids whose adrenocortical function is still impaired
should carry a steroid warning card indicating that they need supplementary systemic
steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major
intercurrent illness, surgery, trauma, etc.
Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks
allergies such as allergic rhinitis or eczema previously controlled by systemic drug.
Paradoxical bronchospasm with an immediate increase of wheezing or other
symptoms of bronchoconstriction after dosing should be treated with an inhaled shortacting bronchodilator, which usually results in quick relief. 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).

Patients inhaler technique should be checked regularly to make sure that inhaler
actuation is synchronised with inhaling to ensure optimum delivery to the lungs.
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).
4.5

Interaction with other medicinal products and other forms of interaction
In vitro data indicate that CYP3A4 is the major enzyme involved in the
metabolism of the active metabolite of ciclesonide M1 in man.
In a drug-drug interaction study at steady state with ciclesonide and
ketoconazole as a potent CYP3A4 inhibitor, the exposure to the active
metabolite M 1 increased approximately 3.5-fold, whereas the exposure to
ciclesonide was not affected. Therefore the concomitant administration of
potent inhibitors of CYP 3A4 (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

Pregnancy and lactation
There are no adequate and well-controlled studies in pregnant women.
In animal studies glucocorticoids have been shown to induce malformations
(see section 5.3). This is not likely to be relevant for humans given
recommended inhalation doses. As with other glucocorticoids, ciclesonide
should only be used during pregnancy if the potential benefit to the mother
justifies the potential risk to the fetus. 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.
It is unknown whether inhaled ciclesonide is excreted in human breast milk.
Administration of ciclesonide to women who are breastfeeding should only be
considered if the expected benefit to the mother is greater than any possible
risk to the child.

4.7

Effects on ability to drive and use machines
Inhaled ciclesonide has no or negligible influence on the ability to drive and
use machines.

4.8

Undesirable effects

Approximately 5% of patients experienced adverse reactions in clinical trials with
Alvesco given in the dose range 40 to 1280 micrograms per day. In the majority of
cases, these were mild and did not require discontinuation of treatment with Alvesco.
Frequency

System Organ Class
Cardiac Disorders
Gastrointestinal
Disorders
General disorders and
administration site
conditions
Immune System
Disorders
Infections and
infestations
Nervous System
Disorders
Psychiatric Disorders

Uncommon
(>1/1,000, <1/100)

Nausea, vomiting*
Bad taste
Application site
reactions
Application site
dryness

Rare
(1/10,000 – 1/,1000)

Unknown

Palpitations**
Abdominal pain*
Dyspepsia*

Angioedema
Hypersensitivity
Oral fungal
infections*
Headache*

Dysphonia
Cough after
inhalation*
Paradoxical
bronchospasm*
Skin and subcutaneous Eczema and rash
tissue disorders
Vascular disorders

Psychomotor
hyperactivity,
sleep disorders,
anxiety,
depression,
aggression,
behavioural
changes
(predominantly in
children)

Respiratory, thoracic
and mediastinal
disorders

*
**

Hypertension

Similar or lower incidence when compared with placebo
Palpitations were observed in clinical trials in cases mostly confounded with
concomitant medication with known cardiac effects (e.g. theophylline or
salbutamol).

Paradoxical bronchospasm may occur immediately after dosing and is an unspecific
acute reaction to all inhaled medicinal products, which may be related to the active
substance, the excipient, or evaporation cooling in the case of metered dose inhalers.
In severe cases, withdrawal of Alvesco should be considered.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses
prescribed for prolonged periods. Possible systemic effects include Cushing's
syndrome, Cushingoid features, adrenal suppression, growth retardation in children
and adolescents, decrease in bone mineral density, cataract, glaucoma (see also
section 4.4).
4.9

Overdose
Acute:
Inhalation by healthy volunteers of a single dose of 2880 micrograms of
ciclesonide was well tolerated.
The potential for acute toxic effects following overdose of inhaled ciclesonide
is low. After acute overdosage no specific treatment is necessary.
Chronic:
After prolonged administration of 1280 micrograms of ciclesonide, no 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Other drugs for obstructive airway diseases,
Inhalants, Glucocorticoids, ATC Code: R03B A08
Ciclesonide exhibits low binding affinity to the glucocorticoid-receptor. Once
orally inhaled, ciclesonide is enzymatically converted in the lungs to the
principal metabolite (C21-des-methylpropionyl-ciclesonide) which has a
pronounced anti-inflammatory activity and is thus considered as the active
metabolite.
In four clinical trials, ciclesonide has been shown to reduce airway
hyperresponsiveness to adenosine monophosphate in hyperreactive patients
with maximal effect observed at the dose of 640 micrograms. In another trial,
pretreatment 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.
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 1,280 micrograms/day did not

statistically significantly lower the 24-hour time averages of plasma cortisol
(AUC(0-24)/24 hours) nor was a dose-dependent effect seen.
In a clinical trial involving 164 adult male and female asthmatic patients,
ciclesonide was given at doses of 320 micrograms or 640 micrograms/day
over 12 weeks. After stimulation with 1 and 250 micrograms cosyntropin, no
significant changes in plasma cortisol levels were observed versus placebo.
Double-blind placebo-controlled trials of 12-weeks duration in adults and
adolescents have shown that treatment with ciclesonide resulted in improved
lung function as measured by FEV1 and peak expiratory flow, improved
asthma symptom control, and decreased need for inhaled beta-2 agonist.
In a 12-week study of 680 severe asthmatics, previously treated with
500-1,000 micrograms fluticasone propionate per day or equivalent, 87.3%
and 93.3% of patients remained exacerbation-free during treatment with 160
or 640 micrograms of ciclesonide, respectively. At the end of the 12 week
study period, the results showed a statistically significant difference between
the doses of 160 micrograms and 640 micrograms/day ciclesonide with regard
to the occurrence of an exacerbation after the first day of the study: 43
patients/339 (= 12.7%) in the 160 micrograms/day group and 23 patients/341
(6.7%) in the 640 micrograms/day group (Hazard ratio=0.526; p= 0.0134).
Both ciclesonide doses resulted in comparable FEV1 values at 12 weeks.
Treatment-related adverse events were seen in 3.8% and 5% of patients treated
with 160 or 640 micrograms per day of ciclesonide respectively. No study was
performed to compare 160 micrograms, 320 micrograms and 640 micrograms
daily dose in patients with severe asthma.

5.2

Pharmacokinetic properties
Ciclesonide is presented in HFA-134a propellant and ethanol as a solution
aerosol, which demonstrates a linear relationship between different doses, puff
strengths and systemic exposure.
ABSORPTION:
Studies with oral and intravenous dosing of radiolabeled ciclesonide have
shown an incomplete extent of oral absorption (24.5%).The oral
bioavailability of both ciclesonide and the active metabolite is negligible
(<0.5% for ciclesonide, <1% for the metabolite). Based on a γ-scintigraphy
experiment, lung deposition in healthy subjects is 52%. In line with this figure,
the systemic bioavailability for the active metabolite is >50% by using the
ciclesonide metered dose inhaler. As the oral bioavailability for the active
metabolite is <1%, the swallowed portion of the inhaled ciclesonide does not
contribute to systemic absorption.

DISTRIBUTION:
Following intravenous administration to healthy subjects, the initial
distribution phase for ciclesonide was rapid and consistent with its high
lipophilicity. The volume of distribution averaged 2.9 l/kg. The total serum
clearance of ciclesonide is high (average 2.0 l/h/kg) indicating a high hepatic
extraction. The percentage of ciclesonide bound to human plasma proteins
averaged 99%, and that of the active metabolite 98-99%, indicating an almost
complete binding of circulating ciclesonide/active metabolite to plasma
proteins.
METABOLISM:
Ciclesonide is primarily hydrolysed to its biologically active metabolite by
esterase enzymes in the lung. Investigation of the enzymology of further
metabolism by human liver microsomes showed that this compound is mainly
metabolized to hydroxylated inactive metabolites by CYP3A4 catalysis.
Furthermore, reversible lipophilic fatty acid ester conjugates of the active
metabolite were detected in the lung.
EXCRETION:
Ciclesonide is predominantly excreted via the faeces (67%), after oral and
intravenous administration, indicating that excretion via the bile is the major
route of elimination.
Pharmacokinetic characteristics in patients:
ASTHMATIC PATIENTS
Ciclesonide shows no pharmacokinetic changes in mild asthmatic patients
compared to healthy subjects.
RENAL OR HEPATIC INSUFFICIENCY, ELDERLY
According to population pharmacokinetics, age has no impact on the systemic
exposure of the active metabolite.
Reduced liver function may affect the elimination of corticosteroids. In a study
including patients with hepatic impairment suffering from liver cirrhosis, a
higher systemic exposure to the active metabolite was observed.
Due to the lack of renal excretion of the active metabolite, studies on renal
impaired patients have not been performed.

5.3

Preclinical safety data
Preclinical data with ciclesonide reveal no special hazard for humans based on
conventional studies of safety pharmacology, repeated dose toxicity,
genotoxicity, or carcinogenic potential.
In animal studies on reproductive toxicity, glucocorticosteroids have been
shown to induce malformations (cleft palate, skeletal malformations).
However, these animal results do not seem to be relevant for humans given
recommended doses.
A treatment-related effect on the ovaries (namely atrophy) was observed at the
top dose in two 12-month studies in dogs. This effect occurred at systemic
exposures 5.27 - 8.34 times those noted at the 160µg daily dose. The relevance
of this finding to humans is unknown.
Animal studies with other glucocorticoids indicate that administration of
pharmacological doses of glucocorticoids during pregnancy may increase the
risk for intrauterine growth retardation, adult cardiovascular and/or metabolic
disease and/or permanent changes in glucocorticoid receptor density,
neurotransmitter turnover and behaviour. The relevance of these data to
humans administered ciclesonide by inhalation is unknown.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Norflurane (HFA-134a)
Ethanol, anhydrous

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
30 metered actuations – 1 year
60 and 120 metered actuations - 3 years.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.
The container contains a pressurised liquid. Do not expose to temperatures
higher than 50°C.
The container should not be punctured, broken or burnt even when apparently
empty.

6.5

Nature and contents of container
The inhaler comprises a pressurized container made from aluminium and is
sealed with a metering valve, mouthpiece, and cap.
30 metered actuations
60 metered actuations
120 metered actuations
[Not all pack sizes may be marketed]

6.6

Special precautions for disposal
Patients should be carefully instructed in the proper use of their inhaler (see
Patient Information Leaflet).
As with most inhaled medicinal products in pressurised containers, the
therapeutic effect of this medicinal product may decrease when the container
is cold. However, Alvesco® delivers a consistent dose from –10°C to 40°C.

7

MARKETING AUTHORISATION HOLDER

Takeda GmbH
Byk-Gulden-Str. 2
D-78467 Konstanz
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 31752/0005

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
16/04/2004 / 28/09/2009

10

DATE OF REVISION OF THE TEXT
15/02/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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