1. NAME OF THE MEDICINAL PRODUCT
Cilclesonide  Aerosol
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
actuation (delivered dose from the mouthpiece) contains 80 micrograms of ciclesonide. .
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 Plus 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 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 M1 increased approximately 3.5fold, 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
4.5 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 breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
4.6 Effects on ability to drive and use machines
Inhaled ciclesonide has no or negligible influence on the ability to drive and use machines.
4.7Overdose
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 24hour 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 24hour 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 12weeks 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 beta2 agonist.
In a 12week study of 680 severe asthmatics, previously treated with 5001,000 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 HFA134a 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 9899%, 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 12month studies in dogs. This effect occurred at systemic exposures 5.278.34 times those noted at the 160 μg 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.