Alvesco

Interactions with herbal products have not been established.

Interactions with food have not been established. Drug-food interactions are unlikely for inhaled corticosteroids.

Interactions with laboratory tests have not been established. Drug-laboratory interactions are unlikely for inhaled corticosteroids.

Ciclesonide is not expected to influence the metabolism of other drugs.

In vitro data indicate that CYP3A4 is the major enzyme involved in the metabolism of the active metabolite of ciclesonide (M1) in man.

The serum levels of ciclesonide and its active metabolite M1, are low. However, co-administration with a potent inhibitor of the cytochrome P 450 3A4 system (e.g. itraconazole, ritonavir or nelfinavir) should be considered with caution because there might be an increase in ciclesonide/active metabolite serum levels, as was observed when orally inhaled ciclesonide was concomitantly administered with ketoconazole (see Drug-Drug Interactions). The risk of clinical adverse effect (e.g. cushingoid syndrome) cannot be excluded.

The recommended starting dose of Alvesco therapy for most patients, whether previously maintained on either bronchodilators alone or inhaled corticosteroids, is 100 to 200 µg once daily.

At present there is limited efficacy data regarding the use of Alvesco in patients <6 years of age and therefore Alvesco is not recommended for patients younger than 6 years.

Symptoms can start to improve with Alvesco within 24 hours of treatment. Clinically, Alvesco has been shown to improve lung function as measured by FEV₁, peak expiratory flow, improved asthma symptom control, reduced exacerbations, and decreased need for inhaled beta-2 agonists.

It is important to gain control of asthma symptoms and optimize pulmonary function as soon as possible. If there has been no improvement within one to two weeks, the patient should consult with their physician. Due to its prophylactic nature, Alvesco should be taken regularly even when patients are asymptomatic. The patient should be aware that the benefit of Alvesco depends on regular use even when they are experiencing no symptoms. When patient symptoms remain under satisfactory control, the dose of Alvesco should be titrated to the lowest dose at which effective control of asthma is maintained. Patients should be instructed to seek medical attention if their asthma symptoms worsen, or if their need for rescue medication increases.

Dose adjustments are not necessary in elderly patients, patients with liver impairment and patients with renal impairment.

The patient should be in a relatively stable phase. A high dose of Alvesco should be given in combination with the oral steroid for about 10 days. Then the oral steroid should be gradually reduced to the lowest possible level. The gradual withdrawal of the systemic steroid is started by reducing the daily dose by 1.0 mg of prednisone (or equivalent of another corticosteroid) at seven day intervals if the patient is under close observation. If close observation is not feasible, the withdrawal of the systemic steroid should be more gradual at approximately 1.0 mg of the daily dose of prednisone (or equivalent) every ten days. If withdrawal symptoms appear, the previous dose of the systemic drug should be resumed for a week before any further decrease is attempted.

The recommended starting dose of Alvesco therapy for most patients, whether previously maintained on either bronchodilators alone or inhaled corticosteroids, is 400 µg once daily.

Alvesco is for oral inhalation use only. To ensure the proper dosage and administration of the drug, the patient must be instructed by a physician or other health professional in the use of the inhalation aerosol (see Information for the Patient). Inhaler technique of patients should be checked regularly to make sure that correct method is used and inhaler actuation is synchronized with inhalation to ensure optimum delivery to the lungs.

In patients who find co-ordination of a pressurized metered dose inhaler difficult, a spacer device (AeroChamber Plus) may be used with Alvesco.

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 Alvesco is a solution aerosol. The mouthpiece should be cleaned with a dry tissue or cloth weekly. No part of the inhaler should be washed or put into water.

Patients should be instructed to use the following technique to administer their medication:

• Instruct the patient to remove the mouthpiece cover, place the inhaler in their mouth, close their lips around the mouthpiece, and breathe in slowly and deeply.

  
  

• After starting to breathe in through the mouth, the top of the inhaler should be pressed down.

  
  

• Then, patients should move the inhaler away from their mouth, and hold their breath for about 10 seconds, or as long as is comfortable.

  
  

• The patient should not breathe out into the inhaler.

  
  

• Finally, patients should breathe out slowly, and replace the mouthpiece cover.

It is very important that ciclesonide is used regularly. If a dose is missed, the next dose should be taken when it is due.

contusion (0.1%).

nausea (0.2%), dry mouth (0.1%), dyspepsia (0.1%).

Very rare reports of immediate or delayed hypersensitivity reactions such as angioedema with swelling of lips, tongue and pharynx as well as increased intraocular pressure in susceptible patients.

Examination of the percentage of patients with normal values at baseline and values above or below the normal range at the end of treatment did not demonstrate any trends with respect to changes in hematology and biochemistry values. See Less Common Clinical Trial Adverse Drug Reactions (≥0.1% to <1%).

The incidence of possibly treatment-related adverse events was generally comparable among the Alvesco dose groups, with the exception of respiratory, thoracic and mediastinal disorders which showed a trend towards dose dependency. This could be due to the fact that the higher dose groups tended to include patients with more severe asthma.

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

cataract subcapsular (0.1%).

pharyngolaryngeal pain (0.4%), throat irritation (0.3%), dry throat (0.1%).

No safety signals specific for gender or for age were found in clinical trials.

The following adverse reactions (assessed as possibly related to treatment by the investigator and/or sponsor) were reported in clinical trials with Alvesco (placebo-controlled, active-controlled and open label studies):

oral candidiasis (0.6%), candidiasis (0.1%), oral fungal infection (0.1%), pharyngitis (0.1%).

headache (0.4%), dysgeusia (0.3%), dizziness (0.1%).

Inhaled corticosteroid therapy may be associated with dose dependent increases in incidence of ocular complications, reduced bone density, suppression of HPA axis responsiveness to stress, and inhibition of growth velocity in children. Although such events have been associated with inhaled corticosteroid therapy, no significant difference was detected between inhaled Alvesco and placebo on HPA function and serum cortisol levels.

Glaucoma may be exacerbated by inhaled corticosteroid treatment for asthma or rhinitis. In patients with established glaucoma who require long-term inhaled corticosteroid treatment, it is prudent to measure intraocular pressure before commencing the inhaled corticosteroid and to monitor it subsequently. In patients without established glaucoma, but with a potential for developing intraocular hypertension, intraocular pressure should be monitored at appropriate intervals. In all patients who are receiving long-term inhaled corticosteroid therapy, intraocular pressure should be monitored at appropriate intervals (see Warnings and Precautions, Monitoring and Laboratory Tests).

In elderly patients treated with inhaled corticosteroids, the prevalence of posterior subcapsular and nuclear cataracts is probably low but increases in relation to the daily and cumulative lifetime dose. Cofactors such as smoking, ultraviolet B exposure, or diabetes may increase the risk.

A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow growth of all children taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if any child’s or adolescent’s growth appears slowed. In a one-year study, Alvesco was shown to have no effect on growth rates compared to placebo when administered to pediatric patients at doses of up to 200 µg per day.

Osteoporosis and bone fracture are complications of long term asthma treatment with parenteral or oral steroids. Inhaled corticosteroid therapy has also been associated with dose dependent bone loss, although the risk is much less with inhaled therapy than with oral and parenteral therapy.

ALT increased (0.1%), gamma-glutamyltransferase increased (0.1%), weight increased (0.1%).

The clinical trial safety database for Alvesco in pediatric patients consists of a total of 3754 children 4-11 years of age treated with Alvesco, 50 to 200 µg per day, in clinical studies ranging in duration from 2 weeks to 1 year. The incidence of possibly treatment related adverse events was similar in frequency and nature to that seen in adults and adolescents. The most commonly reported adverse drug reaction was headache (0.5%).

palpitations (0.1%).

Based on the pharmacokinetic characteristics obtained in patients older than 65 years of age, dose adjustment is not necessary in elderly patients.

At present, there is limited data regarding the use of Alvesco in patients <6 years of age and therefore Alvesco is not recommended for patients younger than 6 years.

At present, there is limited data regarding the use of Alvesco in patients <6 years of age and therefore Alvesco is not recommended for patients younger than 6 years.

Therapeutic dosages of inhaled corticosteroids may cause the appearance of C. albicans (thrush) in the mouth and throat. The rate reported of candidiasis in clinical trials with Alvesco was low (0.6%, see Adverse Reactions). The development of pharyngeal and laryngeal candidiasis is a cause for concern because the extent of its penetration into the respiratory tract is unknown. Adequate oral hygiene is of primary importance in minimizing overgrowth of micro-organisms such as C. albicans. Patients may find it helpful to rinse and gargle with water after using Alvesco. Symptomatic candidiasis can be treated with topical anti-fungal therapy while still continuing to use Alvesco.

The long-term effects of ciclesonide in human subjects are still unknown. In particular, the local effects of the drug on developmental or immunologic processes in the mouth, pharynx, trachea, and lungs are unknown. There is also no information about the possible long-term systemic effects of the agent (see Monitoring and Laboratory Tests).

There is an enhanced effect of corticosteroids on patients with cirrhosis.

There are no adequate and well controlled studies in pregnant women. However, serum concentrations of ciclesonide are generally very low following inhaled administration; thus, fetal exposure is expected to be negligible and the potential for reproductive toxicity low. As with other inhaled corticosteroids, ciclesonide should only be used during pregnancy when the potential benefit to the mother justifies the potential risk to the mother, fetus or infant. Infants born to mothers who received corticosteroids during pregnancy should be observed carefully for hypoadrenalism.

The extent of exposure in pregnancy during clinical trials: Very Limited: individual cases only.

Particular care is needed in asthmatic patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred during and after transfer. For the transfer of patients being treated with oral corticosteroids, Alvesco inhalation aerosol should first be added to the existing oral steroid therapy, which is then gradually withdrawn. Patients with adrenocortical suppression should be monitored regularly and the oral steroid reduced cautiously. Some patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled ciclesonide.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections, particularly gastroenteritis. Although Alvesco inhalation aerosol may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies. The physician may consider supplying oral steroids for use in times of stress (e.g. worsening asthma attacks, chest infections, surgery). During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning and evening cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal only if it falls at or near the normal mean level.

Transfer of patients from systemic steroid therapy to Alvesco inhalation aerosol may unmask allergic conditions outside the pulmonary tract that were previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema. These allergies should be symptomatically treated with anti-histamine and/or topical preparations, including topical steroids.

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 should be sought. In this situation, patients should be reassessed and consideration given to the need for increased anti-inflammatory treatment therapy (either higher doses of Alvesco or a course of oral corticosteroids). Severe asthma exacerbations should be managed according to standard medical practice.

Based on the pharmacokinetic characteristics obtained in patients with hepatic insufficiency, dose adjustment is not necessary in this population. There is limited 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.

As with other inhalation therapy, paradoxical bronchospasm may occur which is characterized by an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator to relieve acute asthmatic symptoms. Alvesco should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted.

Based on the pharmacokinetic characteristics obtained in patients older than 65 years of age, dose adjustment is not necessary in this population.

Patients who are on drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with intramuscular pooled immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids may mask some signs of infections and new infections may appear. A decreased resistance to localised infections has been observed during corticosteroid therapy. This may require treatment with appropriate therapy or stopping the administration of ciclesonide until the infection is eradicated.

It is essential that patients be instructed that Alvesco is a preventative agent which must be taken daily at the intervals recommended by their doctors and is not to be used as acute treatment for an asthmatic attack. Patients should be advised to inform subsequent physicians of the prior use of corticosteroids. Treatment with Alvesco should not be stopped abruptly, but tapered off gradually.

Due to the lack of renal excretion of the active metabolite, dose adjustment should not be necessary in renally impaired patients, however, specific studies in this patient group have not been performed.

In rare cases, patients on inhaled corticosteroid therapy may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids, and cases of serious eosinophilic conditions have been reported in this clinical setting.

Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between ciclesonide and these underlying conditions has not been established.

As with all inhaled corticosteroids, during long-term therapy, HPA axis function (e.g. blood cortisol levels) and effects on the eye (examination for cataracts, increased intraocular pressure and glaucoma) should be assessed periodically by a specialist. See Systemic Effects.

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 increased intraocular pressure, with or without glaucoma. Therefore, it is important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Acetylsalicylic acid should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

It is unknown if ciclesonide and/or its active metabolite is excreted in human milk. In rats, however, very low levels of ciclesonide and/or its metabolites (<0.05% of dose) were found to be excreted into the milk following intravenous or oral administration. As with other inhaled corticosteroids, Alvesco should only be used in nursing women when the potential benefit to the mother justifies the potential risk to the mother and/or infant.

There is an enhanced effect of corticosteroids on patients with hypothyroidism.

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 (1.8 to 2.8 times) to the active metabolite was observed.

In a comparison between one study in elderly subjects and another study in young healthy subjects, there was an approximately 2-fold increase in the rate and extent of exposure to the active metabolite in elderly patients. However, in a population pharmacokinetic analysis of 9 studies, age did not impact the clearance or volume of distribution of the active metabolite.

Following intravenous administration to healthy subjects, 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 is 99% and that of the active metabolite is greater than 98%. Only the unbound drug in the systemic circulation (approximately 1-2%) is available for further systemic pharmacodynamic effect. The active metabolite showed no accumulation in red blood cells, as could be concluded from high plasma/whole blood ratio of 1.5-1.6 at 0.5-6 hours post-dosing.

Studies with oral and intravenous dosing of radiolabelled drug have shown low oral absorption (24.5%). When inhaled the oral bioavailability of both ciclesonide and the active metabolite is negligible (<0.5% for ciclesonide, <1% for the active metabolite). Based on a γ-scintigraphy experiment, lung deposition in healthy subjects is 52%. The systemic bioavailability for the active metabolite is >50% when using the ciclesonide metered-dose inhaler. As the oral bioavailability for the active metabolite is <1%, the swallowed portion of the inhaled drug effectively does not contribute to the systemic absorption. Ciclesonide undergoes extensive first pass metabolism. See Table 4 for information regarding the pharmacokinetic characteristics (AUC, T_max and C_max) of ciclesonide following single and repeated dose administration.

Ciclesonide exhibits low binding affinity to the glucocorticoid receptor and is pharmacologically inactive. Once inhaled, ciclesonide is converted by esterases in the lungs to its active metabolite, 21 des-methylpropionyl-ciclesonide (M1), which is a potent glucocorticoid that binds to glucocorticoid receptors in the lung resulting in local pronounced anti-inflammatory activity.

After oral and intravenous administration, ciclesonide is predominantly excreted via the faeces (78 and 68%, respectively), indicating that excretion via the bile is the major route of elimination. After intravenous administration, the clearance of ciclesonide was 152±37 L/h and that of the active metabolite, M1 (assuming full conversion from ciclesonide) was 228±65 L/h. The half-life estimated from the terminal elimination phase after inhaled administration of ciclesonide was approximately 6 h.

Due to the low rate of renal excretion of ciclesonide metabolites, studies on renally impaired patients have not been performed.

Summary of the Pharmacokinetic Parameters of Ciclesonide Active Metabolite (M1) in Healthy Subjects Following Inhalation of 400 µg Ciclesonide (n=18), Mean Values (Standard Deviation)

Ciclesonide is a prodrug and is hydrolysed to its pharmacologically active metabolite by esterase enzymes primarily in the lungs. 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. Lipophilic fatty acid ester conjugates of the active metabolite in the lung were detected using in vitro techniques.

The active metabolite of ciclesonide (M1) exhibits high receptor affinity. Ciclesonide possesses a unique combination of properties that limits systemic exposure to the active drug including: the conversion to the active metabolite predominantly in the lung, high lung deposition, reversible formation of fatty acid conjugates of M1 in lung tissue slices, high clearance, low oral bioavailability, high protein binding, and low receptor affinity of metabolites other than M1. The clinical effects of ciclesonide on the HPA function and serum cortisol levels were investigated and, at therapeutic doses, no significant difference was detected between inhaled ciclesonide and placebo.

In two 12 week clinical studies investigating the safety and efficacy of Alvesco in asthmatic patients between 4-11 years of age, serum samples were taken from 53 patients for pharmacokinetic analysis. The pharmacokinetics of the active metabolite M1 were found to be similar to adults.