Ciclesonide

Ciclesonide belongs to the pharmacological class Corticosteroids. Ciclesonide appears to have anti-inflammatory and immunomodulatory effects in the pulmonary system. Ciclesonide is found to be rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP), which is said to mediate anti-inflammatory actions. Ciclesonide has shown to inhibit the expression of multiple genes that encode pro-inflammatory factors, such as chemokines, cytokines and adhesion molecules that are activated during the chronic inflammatory process

Ciclesonide has been found to be approved for relieving symptoms and also for the maintenance and treatment of episodes of antenatal fetal maturation, bursitis, dermatologic conditions, foot disorders, multiple sclerosis, rheumatoid and osteoarthritis, tenosynovitis, peritendinitis, dermatoses, and plaque psoriasis

Ciclesonide is completely and rapidly absorbed. Ciclesonide achieved a steady state volume of distribution of 94,584±23,539 mL. There are 6 metabolites of Ciclesonide and the metabolic processes include 6β hydroxylation, 11β-hydroxyl oxidation, and also reduction of the C-20 carbonyl group followed by removal of the side chain. The route of the elimination was primarily through urine.

The common side effects associated with Ciclesonide are irregular heartbeat, shortness of breath, dizziness, blurred vision, weight gain, slow wound healing, etc.

Ciclesonide is available in the form of oral soluble tablets and Topical cream. Ciclesonide is available in U.S., Canada,E.U. , India, Australia, Japan.

Ciclesonide belongs to the pharmacological class of Corticosteroids. Ciclesonide appears to have anti-inflammatory and immunomodulatory effects in the pulmonary system.

Ciclesonide appears to act in both genomic and non-genomic pathways.

The genomic pathway is found to be slower and occurs when the glucocorticoids activate glucocorticoid receptors and this initiates downstream effects which promote transcription of anti-inflammatory genes including IL-1-receptor antagonist, phosphoenolpyruvate carboxykinase (PEPCK), and tyrosine aminotransferase (TAT).On the other hand, the nongenomic pathway is found to be able to elicit a quicker response by platelet ,modulating T-cell,and monocyte activity through the use of existing membrane-bound receptors and laos the second messengers.

Ciclesonide has been found to be approved for relieving symptoms and also for the maintenance and treatment of episodes of asthma and allergic rhinitis.

The half-life of Ciclesonide was found to be about 11 hours after oral and intramuscular administration.

Onset the of action of Ciclesonide occurs within two hours and lasts upto about 7 days.

Ciclesonide can be used in the treatment of

• Asthma
• Allergic Rhinitis

Ciclesonide is approved for use in the following clinical indications:

• Asthma
• Allergic Rhinitis

Oral Inhalation

Aerosol or Metered Dose Inhalation.

1. The cap is removed from the MDI and chamber and Shaken well.

2. The MDI is inserted inside the open end of the chamber opposite to the the mouthpiece.

3. The mouthpiece of the chamber is placed between your teeth and your lips are sealed tightly around it.

4. Now breathe out completely.

5. Then press the canister once.

6. Now breathe in slowly and completely through your mouth. If one hears a "horn-like" sound, then the person is breathing too quickly and needs to slow down.

7. Now hold your breath for 10 seconds and count to 10 slowly in order to allow the medication to reach the lungs.

8. The above steps are repeated for each puff ordered by the medical practitioners and wait about 1 minute in between puffs.

9. Lastly, replace the cap on your MDI when finished.

Nasal Inhalation

1. The top of the canister is pressed down four times or until a fine spray comes out in case one has not used this medicine for 7 days in a row, one must prime the spray, or if it is being used for the first time

2. After the nasal spray is primed, there will only be 120 doses or sprays.

3. The nose is gently blown before using the spray and head is tilted slightly backward and the tip of the nosepiece is inserted into one's nostril.

4. The opposite nostril is closed with a finger and one spray is released at the same time air is breathed in gently through the nostril.

5. Breath is held for a few seconds then air is breathed out slowly through the mouth.

6. The opposite nostril is sprayed using the same steps.

7. The nose should not be blown after using the spray.

Oral Inhalation: 80mcg, 160mcg,320mcg

Nasal Inhalation:37 mcg or 50mcg per spray

Oral and Nasal Inhalation.

• Dosage Adjustments in Pediatric Patients:

Allergic or Inflammatory conditions: Intramuscular injection: Initial dose of 0.02 to 0.3 mg/kg/day which is 3 or 4 divided doses.

Severe Infantile hemangioma: 6mg/ml injection along with triamcinolone injection. Doses reported to be administered in the range of 1.5 to 18 mg/kg/ml for every 8 to 14 weeks or 6 to 25 weeks

Dermatoses: apply 0.1% or 0.05% beclomethasone ointment at the affected area for about three time’s day.

Smoking cessation and maintaining health is a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Alcohol should be avoided in the patient especially with an underlying liver disorder or liver dysfunction

Diet containing food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, refined and high energy-dense foods, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions is needed to be individualized as per the patient's requirements.

Ciclesonide may be contraindicated under the following conditions:

• Hypersensitivity to the ingredients of the medication
• In the primary treatment of status asthmaticus.

The treating physician should closely monitor the patients and keep pharmacovigilance as follows:

Local Effects

In the clinical trials, the development of localized infections of pharynx and mouth with Candida albicans has found to have occurred in thirty two of 3038 patients treated with ciclesonide. Out of the thirty two reported cases, twenty occurred inon ethopatients treated with a total daily dose of three hundred and twenty mcg of ciclesonide or higher. Most cases of candida infection were found to be mild to moderate. When such an infection is found to have developed, it should be treated with appropriate systemic or local (usand three hunfi.e., oral antifungal) therapy while remaining on treatment with ciclesonide, but at times therapy with ciclesonide may need to be interrupted. It is advised that patients should rinse their mouth after inhalation of ciclesonide.

Acute Asthma Episodes

As Ciclesonide is not a bronchodilator and also is not indicated for rapid relief of bronchospasm or the other acute episodes of asthma, hence patients should be instructed to contact their general physician immediately if episodes of asthma which are not responsive to their usual doses of the bronchodilators had occured during the course of treatment with ciclesonide. During such episodes, patients might undergo therapy with oral corticosteroids.

Immunosuppression

Persons who are using drugs which suppresses the immune system are more susceptible to many infections than healthy individuals. Measles and chickenpox, for example, can have a more fatal or serious course in susceptible children or adults using corticosteroids. In such children or adults who had not had these diseases or been properly immunized, some care should be taken to avoid exposure.

Transferring Patients from Systemic Corticosteroid Therapy

Particular care should be taken patients who are transferred from systemically active corticosteroids to ciclesonide because deaths due to adrenal insufficiency had occurred in asthmatic patients during as well as after transfer from systemic corticosteroids into less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, several months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Hypercorticism and Adrenal Suppression

Ciclesonide will often help control asthma symptoms with less suppression of hypothalamic-pituitary-adrenal function than the therapeutically similar oral doses of prednisone.

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) had been observed with long-term administration of products which contain inhaled corticosteroids. The clinical significance of small changes in bone mineral density with regard to long-term outcomes is unknown.

Effect on Growth

Orally inhaled corticosteroids might cause a reduction in growth velocity when it is administered to pediatric patients. Monitor the growth of pediatric patients receiving ciclesonide routinely. To minimize the systemic effects of ciclesonide, each patient's dose should be titrated to the lowest dosage that effectively controls his/her symptoms.

Glaucoma and Cataracts

Glaucoma also called as increased intraocular pressure, and cataracts had been reported followed the administration of inhaled corticosteroids including ciclesonide. Therefore, close monitoring should be in patients with a history of increased glaucoma,with a change in vision or intraocular pressure, and/or cataracts.

Bronchospasm

As with ciclesonide medications, bronchospasm, with an immediate increase in wheezing, might occur after dosing. If bronchospasm occurs followed by dosing with ciclesonide, this condition should be treated immediately with a fast-acting inhaled bronchodilator.

Avoid alcohol usage while on Ciclesonide medication as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision etc.

It is unknown whether ciclesonide is secreted in human milk. In a animal study with lactating rats, levels of ciclesonide were recovered in milkwere minimal but detectable. Caution should be excercised when ciclesonide is administered to nursing women.

Pregnancy

Teratogenic Effects: Pregnancy Category C

The oral administration of ciclesonide during clinical studiesn in rats up to nine hundred mcg/kg/day which is approximately 10 times the MHDID based on mcg/m2 /day,had produced no teratogenicity or other effects on fetes. However, subcutaneous administration of ciclesonide in rabbits at five mcg/kg/day i.e.less than the MHDID on mcg/m2 /day, or greater produced fetal toxicity. This included cleft palate, skeletal abnormalities including incomplete ossifications, fetal loss, reduced fetal weight, and skin effects. No toxicity was observed at one mcg/kg i.e.less than the MHDID based on mcg/m2. There are found to be no adequate and well-controlled studies in pregnant women. Ciclesonide should be used during pregnancy only if the potential benefits outweighs the potential risks associated to the fetus.

Non-teratogenic Effects: Hypoadrenalism might occur in infants who are born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

No sufficient scientific evidence traceable regarding the use and safety of Ciclesonide in concurrent use with any particular food.

The adverse reactions related to Ciclesonide can be categorized as:

Common

• Sneezing
• Sore throat
• Stuffy or runny nose
• Tightness of chest or wheezing
• Unusual tiredness or weakness
• Chills
• Cough
• Difficulty in breathing
• Ear congestion
• Fever
• Headache
• Loss of voice
• Muscle aches
• Nasal congestion
• Pain or tenderness around eyes and cheekbones
• Shortness of breath or troubled breathing

Rare

• White patches in mouth and/or on tongue
• Sore mouth or tongue

The clinically relevant drug interactions of Ciclesonide is briefly summarized here:

In vitro studies and clinical pharmacology studies had suggested that metabolite des-ciclesonide had no potential for the metabolic drug interactions or protein binding-based drug interactions studies.

In one of the drug interaction studies, co-administration of orally inhaled ciclesonide and also oral ketoconazole, which is a potent inhibitor of enzyme cytochrome P450 3A4, increased the exposure (AUC) of metabolite desciclesonide which is approximately 3.6-fold at steady state, while levels of ciclesonide had remained unchanged.

The common side effects of Ciclesonide include the following:

• Tunnel vision
• Blurred vision
• Worsening asthma symptoms
• Wheezing
• Trouble breathing
• Choking
• Chest tightness
• Sores or white patches in your mouth or throat

Pregnancy

Teratogenic Effects: Pregnancy Category C

The oral administration of ciclesonide during clinical studiesn in rats up to 900 mcg/kg/day which is approximately 10 times the MHDID based on mcg/m2 /day,had produced no teratogenicity or other effects on fetes. However, subcutaneous administration of ciclesonide in rabbits at 5 mcg/kg/day i.e.less than the MHDID on mcg/m2 /day, or greater produced fetal toxicity. This included cleft palate, skeletal abnormalities including incomplete ossifications, fetal loss, reduced fetal weight, and skin effects. No toxicity was observed at 1 mcg/kg i.e.less than the MHDID based on mcg/m2. There are found to be no adequate and well-controlled studies in pregnant women. Ciclesonide should be used during pregnancy only if the potential benefits outweighs the potential risks associated to the fetus.

Non-teratogenic Effects: Hypoadrenalism might occur in infants who are born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Nursing Mothers

It is unknown whether ciclesonide is secreted in human milk. In a animal study with lactating rats, levels of ciclesonide were recovered in milkwere minimal but detectable. Caution should be excercised when ciclesonide is administered to nursing women.

Pediatric Use

The safety and effectiveness of ciclesonide in children under twelve years of age have not been established. Two randomized double-blind placebo-controlled clinical studies had been conducted to evaluate the efficacy of ciclesonide 40, 80, or 160 mcg administered once daily for twelve weeks in patients four to elevan years of age with asthma. These studies included one thousand and eighteen patients previously using either controller therapy i.e.predominantly inhaled corticosteroids) or reliever therapy. The patients had a mean baseline percent which has been predicated FEV1 of 68%. The primary efficacy endpoint was foudn to be morning pre-dose FEV1. Other measures of efficacy which included AM PEF, asthma symptoms, and rescue albuterol use. The studies had showed inconsistent results and did not establish the efficacy of ciclesonide in patients 4 to 11 years of age.

Geriatric Use

Clinical studies of ciclesonide did not include sufficient numbers of patients who were aged 65 years and older to determine whether they respond any different than the younger patients. Other reported clinical experience has not been identified differences in responses between the younger and elderly patients. In general, dose selection for elderly patient should be done with caution, usually which is done with low end dose of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and or other drug therapyor of concomitant disease .

Physician should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of overdosage of Ciclesonide.

Chronic overdosage might result in signs/symptoms of hypercorticism. Ciclesonide had been well tolerated followed by inhalation by healthy subjects of single doses of 2880 mcg. A single oral dose of ciclesonide up to 10 mg of ciclesonide in healthy subjects had been well tolerated and serum cortisol levels had been virtually unchanged as compared with placebo treatment. Adverse reactions were of mild or moderate severity. The median lethal doses in animal studies consists of mice and rats after single oral and intraperitoneal administration were found to be >2000 mg/kg and >200 mg/kg, respectively. These doses are found to be >12000 and >2500 times the MRDID in adults on a mg/m2 basis.

Pharmacodynamics

The effects of ciclesonide by oral inhalation on the HPA axis had been assessed in adults with mild asthma in a twenty nine-day placebo controlled study. 24 hour urinary free cortisol had been assessed in a total of fifty nine adults who were randomized in clinical trials to 320 mcg or 640 mcg ciclesonide, a comparator corticosteroid, or placebo two times a day. At the end of twenty nine days of treatment, the mean (SE) change from baseline in twenty four hour urinary free cortisol was found to be -8.69 (5.6) mcg/day, -4.01 (5.03) mcg/day, and also -8.84 (5.02) mcg/day for the placebo, ciclesonide 640 mcg/day, and ciclesonide 1280 mcg/day, respectively.

Pharmacokinetics

• Absorption

Ciclesonide and des-ciclesonide have foudn to have negligible oral bioavailability which is both are less than 1% due to low gastrointestinal absorption as well as high first-pass metabolism. Serum concentrations of ciclesonide and des-ciclesonide have been measured and compared followed by oral inhalation of 1280 mcg ciclesonide and intravenous administration of 800 mcg ciclesonide. The absolute bioavailability of ciclesonide was found to be 22% and the relative systemic exposure of des-ciclesonide was found to be 63%. The mean Cmax for metabolite des-ciclesonide was foudn to be 1.02 ng/mL i.e.range 0.6-1.5 ng/mL in asthmatic patients followed by a single dose of 1280 mcg by oral inhalation. The mean Cmax i.e.0.369 ng/mL and AUC0-¥ i.e.2.18 ng*hr/mL of des-ciclesonide followed by multiple dose administration of ciclesonide of about 320 mcg once a day increased up to 26% when compared to single dose administration.

• Distribution

Followed by intravenous administration of 800 mcg of ciclesonide, the volumes of distribution of ciclesonide and des-ciclesonide were found to be approximately 2.9 L/kg and 12.1 L/kg, respectively. The percentage of ciclesonide and des-ciclesonide which is bound to human plasma proteins averaged more than e 99% each, with about ≤ 1% of unbound drug which is detected in the systemic circulation. Desciclesonide is not found to be significantly bound to human transcortin.

• Metabolism

Ciclesonide is found to be hydrolyzed to a biologically active metabolite called as des-ciclesonide, by esterases. The metabolite Des-ciclesonide is found to undergoes further metabolism in the liver to form additional metabolites mainly by the enzyme cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by enzyme CYP 2D6. After intravenous administration of 14C-radiolabelled ciclesonide, 19.3% of the resulting radioactivity in the plasma has been accounted for by ciclesonide or metabolite des-ciclesonide; the remainder might be a result of other, as yet, unidentified multiple metabolites.

• Elimination

Followed by intravenous administration of 800 mcg of ciclesonide, the clearance of ciclesonide and the metabolite des-ciclesonide were found to be high which is approximately 152 L/hr and 228 L/hr, respectively. 14C-radiolabelled ciclesonide was predominantly excreted through the feces after intravenous administration i.e.66% indicating that excretion through bile is found to be the major route of elimination. Approximately 20% or less of des-ciclesonide was found to be excreted through urine. The mean half-life of ciclesonide and the metabolite des-ciclesonide was found to be 0.71 hours and 6 to 7 hours respectively. Tmax of desciclesonide occurs at 1.04 hours following inhalation of ciclesonide.

• https://go.drugbank.com/drugs/DB01410
• https://medlineplus.gov/druginfo/meds/a609004.html
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021658s006lbl.pdf
• https://www.astrazeneca.com/media-centre/press-releases/2018/divestment-of-rights-to-alvesco-omnaris-and-zetonna-to-covis-pharma-06112018.html#