Ciclesonide: Innovative Treatment for Allergic Rhinitis

Overview

Ciclesonide is an FDA (Food and Drug Administration) approved corticosteroid medicine for patients suffering from allergic rhinitis. It is available as a nasal spray, and it is applied to the nasal passages to alleviate allergy-related symptoms such as sneezing, a runny or stuffy nose, itching, and congestion in the nasal passages. For people with allergic rhinitis, Ciclesonide works by lessening inflammation in the nasal passages, which helps to reduce the allergic reaction and enhance breathing and general comfort. The important thing to note is that Ciclesonide is a relatively new inhaled steroid. It is a new-generation corticosteroid that has demonstrated efficacy in treating asthma when delivered through a metered-dose inhaler. It is also being tested in humans as an intranasal formulation to help treat allergic rhinitis. The potential of new inhaled steroids like Ciclesonide is apparent. Ciclesonide is effective, safe, and well-tolerated by patients when given as an inactive parent molecule turned into a pharmacologically active metabolite by enzymes in both the upper and lower airways.

How Does Ciclesonide Work?

Allergic rhinitis manifests with symptoms such as sneezing and a congested, runny, or itchy nose. Ciclesonide belongs to a group of medications known as corticosteroids, which effectively reduce and prevent inflammation in the nasal passages, alleviating these symptoms and improving nasal comfort.

Clinical Efficacy and Safety of Ciclesonide for Allergic Rhinitis:

Ciclesonide has proven to be an effective and well-tolerated treatment option for allergic rhinitis, offering convenience and symptom relief for patients suffering from seasonal and perennial allergies. In clinical trials, the once-daily intranasal administration of 200 μg (microgram) of Ciclesonide demonstrated significant effectiveness in treating seasonal allergic rhinitis (AR). Notably, Ciclesonide nasal spray showed similar positive effects on all four components of the total nasal symptom score (TNSS) – nasal congestion, rhinorrhea, nasal itching, and sneezing. Comparisons across studies suggest that the treatment-effect size of Ciclesonide is larger than that of Montelukast and Desloratadine, two other commonly used medications for seasonal AR.

The dosing posology analysis indicated that once-daily morning dosing is suitable for ciclesonide nasal spray, potentially enhancing patient compliance compared to medications requiring more frequent dosing.

In safety and efficacy studies, ciclesonide nasal spray at 100 to 200 μg/day (microgram per day) was well-tolerated and associated with dose-related improvements in relieving nasal symptoms in seasonal AR. The 200 μg/day dose of Ciclesonide nasal spray was identified as the most effective dose for symptom relief.

In treating perennial allergic rhinitis (PAR), intranasal Ciclesonide at 200 μg once daily demonstrated superiority over placebo in controlling daytime and nighttime nasal symptoms. Ciclesonide was well-tolerated, associated with reduced total nasal symptoms, and provided the convenience of once-daily dosing.

Studies have consistently shown that Ciclesonide, administered once daily at a dose of 200 μg per nostril, effectively improves subjective symptoms of allergic rhinitis and rhinal airflow while being well-tolerated at both local and systemic levels.

Overall, Ciclesonide has proven to be an effective and well-tolerated treatment option for allergic rhinitis, offering convenience and symptom relief for patients suffering from seasonal and perennial allergies.

For Patients

What Is Allergic Rhinitis?

An allergic reaction to substances like pollen, dust, animal dander, or particular foods results in the condition known as allergic rhinitis, which is characterized by a group of symptoms affecting the nose. When exposed to these allergens, individuals may experience symptoms such as sneezing, nasal irritation, runny nose, and other discomforts. It is a diagnosis associated with inflammation of the nasal lining, triggered by the body's immune response to allergens. Allergic rhinitis can be seasonal, triggered by specific allergens like pollen or perennial, occurring year-round due to exposure to indoor allergens like dust mites or pet dander.

What Is Ciclesonide?

Adults and teens aged 12 and up can get a prescription for Clesonide nasal aerosol to help with their seasonal and year-round allergy symptoms. It contains Ciclesonide, a synthetic corticosteroid that mimics the body's natural anti-inflammatory substances. When sprayed into the nose, the aerosol can help reduce allergic rhinitis symptoms such as nasal congestion, runny nose, itching, and sneezing. It may also provide relief for red, itchy, and watery eyes. However, the safety and efficacy of Ciclesonide nasal aerosol have not been established in children under 12 years of age.

How Should the Patient Take Ciclesonide?

The patient should take Ciclesonide according to the doctor's instructions, avoiding exceeding the prescribed dose or frequency. This medicine is intended for nasal use only and should not come into contact with the eyes, nasal septum, or skin. The nasal spray should be primed before the first use or if the medicine has not been used for ten days. To use the spray, gently blow the nose, insert the tip into one nostril, and spray while inhaling. Repeat for the other nostril and refrain from blowing the nose for 15 minutes after use. The patient should keep track of the number of sprays used, usually 60 sprays per canister, and discard the medicine after 60 sprays or as indicated by the dose indicator. It is very important to follow these directions for safe and correct use of Ciclesonide.

What Are the Things to Inform the Doctor Before Taking Ciclesonide?

• Inform the doctor about any allergies to Ciclesonide or other nasal corticosteroids.

• Mention all medications, vitamins, supplements, and herbal products being taken, especially Ketoconazole or oral steroids.

• Report a history of tuberculosis, cataracts, glaucoma, untreated infections, or herpes eye infection.

• Notify the doctor of recent nose surgery or injuries.

• Discuss pregnancy, plans to become pregnant, or breastfeeding status with the doctor.

• Inform healthcare professionals about Ciclesonide use before any surgery or dental procedures.

• Follow the doctor's guidance if previously on oral steroids, as the dosage may need adjustment when starting Ciclesonide.

• Be attentive during the transition, reporting any adverse symptoms.

• Be aware that Ciclesonide may weaken the immune system, so avoid contact with sick individuals and maintain good hand hygiene.

• In case of exposure to chickenpox or measles, contact the doctor immediately.

What Are the Side Effects of Ciclesonide?

Side effects of Ciclesonide may include:

• Dry or irritated throat.

• Hoarseness.

• Bad taste in the mouth.

• Coughing.

If an individual is experiencing any of the following serious side effects, they should notify the doctor immediately:

• White patches in the mouth or on the tongue.

• Headache that persists.

• Vision changes.

• Poor wound healing.

• Puffy face.

• Unexpected weight gain.

• Muscle pain or weakness.

• Mental or mood changes, such as depression or agitation.

• Increased thirst or urination.

In rare cases, Ciclesonide may cause a sudden and severe worsening of breathing problems or asthma immediately after use. If experiencing such a sudden worsening of breathing, use the quick-relief inhaler and seek immediate medical help.

Overdose: Overusing Ciclesonide consistently for an extended duration may lead to the following symptoms:

• Swelling in the face and neck.

• Aggravation of acne.

• Increased susceptibility to bruising.

• Excessive fatigue.

• Weakened muscles.

• Irregularities in menstrual periods.

How Should the Patient Store Ciclesonide?

It is best to keep the Ciclesonide inhaler at room temperature, out of reach of children, and away from sources of extreme heat and moisture (like the bathroom). When putting the inhaler away, keep it away from open flames and heat sources. Keep the inhaler out of the sun and the cold. When throwing away the aerosol container, do not poke holes in it or set it on fire.

Always keep any medications out of children's sight and reach. Children may easily open some containers, such as those for eye drops, lotions, patches, and inhalers, because they may not be child-resistant. Ensure safety caps are locked and keep medications up, away, and out of children's sight and reach to prevent accidental consumption by them.

For Doctors

Usage and Indications: Ciclesonide is given to adults and teens 12 years and older to help with the nasal symptoms of seasonal and perennial allergic rhinitis. It is also used to relieve clinical signs of severe equine asthma, previously referred to as recurrent airway obstruction (RAO) or summer pasture-associated recurrent airway obstruction (SPA-RAO).

Dosage and Administration: For adults and adolescents 12 years and older, the recommended dose of Ciclesonide Nasal Aerosol is one spray per nostril once daily, each actuation delivering 37 mcg (microgram) of medication. The maximum daily dose should not exceed one spray in each nostril, amounting to 74 mcg daily. Ciclesonide nasal aerosol should only be administered through the intranasal route.

Clinical Pharmacology

1. Mechanism of Action: Ciclesonide, a glucocorticoid, exerts anti-inflammatory effects through various mechanisms. It can hinder the infiltration of immune cells at the site of inflammation, disrupt mediators involved in the inflammatory response, and dampen humoral immune reactions.

One of the key actions of glucocorticoids is their interaction with phospholipase A2 inhibitory proteins called lipocortins. These lipocortins regulate the production of potent inflammation-inducing molecules like prostaglandins and leukotrienes. By controlling these molecules' biosynthesis, ciclesonide helps reduce the inflammatory reaction.

Moreover, Ciclesonide restricts the dilation and permeability of capillaries in vascular structures, limiting the accumulation of specific immune cells like polymorphonuclear leukocytes and macrophages. It also diminishes the release of vasoactive kinins, contributing to the anti-inflammatory effect.

Recent studies propose that corticosteroids may obstruct the release of arachidonic acid from phospholipids, reducing the formation of prostaglandins. Ciclesonide functions as a glucocorticoid receptor agonist. When it binds to the glucocorticoid receptor, the resulting complex enters the cell nucleus and attaches to numerous glucocorticoid response elements (GRE) within the promoter region of target genes. This binding to DNA regulates the expression of specific genes, suppressing IL2 (interleukin 2) expression, among other effects.

2. Pharmacodynamics and Pharmacokinetics: The acetal side chain of the Ciclesonide molecule has a chiral center, which makes two different epimers with different receptor affinities and rates of metabolism. The R-epimer exhibits a notably higher binding affinity to the glucocorticoid receptor, making it the preferred choice for clinical use. At the same time, the S-epimer differs in these aspects and is not utilized.

Ciclesonide is administered as an inactive parent compound, which is later metabolized by endogenous esterases in the upper and lower airways, transforming into the pharmacologically active metabolite desisobutyryl-Ciclesonide (des-CIC). In vitro studies on rat lungs demonstrate that esterification of des-CIC, forming a pool of active drugs, can lead to sustained anti-inflammatory activity.

On-site activation offers several advantages, including targeted lung activation, minimal systemic adverse effects, and limited oropharyngeal side effects. Ciclesonide's favorable safety profile is attributed to its low oral bioavailability (approximately 1 % for des-CIC), high protein binding (99 %), and significant hepatic clearance.

3. Distribution: After administering ciclesonide intravenously to healthy individuals, the initial distribution phase occurred rapidly, which aligns with its significant lipophilic properties. The average volume of distribution was 2.9 liters per kilogram, indicating the drug's widespread distribution throughout the body. Ciclesonide exhibited high total serum clearance (average 2.0 liters per hour per kilogram), suggesting that it undergoes substantial hepatic extraction, likely during metabolism in the liver.

• Bioavailability: The active metabolite shows a bioavailability of 63 %.

• Absorption: The absorption rate is 52 %.

• Protein Bound: When administered intravenously (IV), it is bound to 99 % of proteins.

• Volume of Distribution (Vd): After IV administration, the Vd is 2.9 L/kg for Ciclesonide and 12.1 L/kg for des-Ciclesonide.

4. Metabolism:

Ciclesonide undergoes a two-step biotransformation process. Initially, it is metabolized by esterases into its active form, des-Ciclesonide. Subsequently, the liver plays a crucial role in further metabolism, primarily through the action of CYP3A4 and, to a lesser extent, CYP2D6 enzymes. In the lung, the main biotransformation pathway involves hydrolysis by esterase enzymes, resulting in the formation of the biologically active metabolite. Studies using human liver microsomes revealed that CYP3A4 is primarily responsible for catalyzing the transformation of ciclesonide into hydroxylated, inactive metabolites. Additionally, reversible lipophilic fatty acid ester conjugates of the active metabolite were identified in the lung.

5. Elimination: The primary route of elimination for Ciclesonide is through the feces, accounting for approximately 66 % of the excretion, following both oral and intravenous administration. This indicates that excretion via the bile is the main pathway for eliminating the drug from the body.

Following IV administration:

6. Half-life: The half-life is 0.71 hours for Ciclesonide and six to seven hours for des-Ciclesonide.

7. Clearance: The clearance rate is 152 L/L/hr for Ciclesonide and 228 L/L/hr for des-Ciclesonide.

8. Excretion: Approximately 66 percent is excreted in feces and 20 percent in urine.

9. Toxicity: Not known.

Contraindications:

Patients with a known hypersensitivity to Ciclesonide should not use Ciclesonide nasal aerosol.

Adverse Effects:

Studies have found that Ciclesonide is generally safe and well-tolerated in healthy volunteers and asymptomatic subjects with seasonal allergic rhinitis (SAR). There is no significant increase in adverse event frequency with higher doses of intranasal Ciclesonide, ranging from 50 to 800 μg/day.

The incidence of treatment-emergent adverse events is comparable between healthy volunteers and subjects with SAR. During the study, the most common adverse effects that were reported were:

• Headache (11 %).

• Fatigue (7 %).

• Rhinitis (7 %).

• Nasopharyngitis (11 %).

Most adverse events (97 %) experienced by participants were mild in intensity.

Headaches, stuffy noses, and rhinorrhea were the most common side effects that may or may not have been caused by the study drug. No adverse events were considered related to the study medication. There were no reports of serious side effects during the study.

Furthermore, the adverse effects with an incidence rate between 1 % and 10 % include epistaxis (4.9 %), ear pain (2.2 %), facial edema (3 %), urticaria (3 %), oral candidiasis (3 %), back pain (3 %), extremity pain (3 %), conjunctivitis (3 %), upper respiratory infection (9 %), gastroenteritis (3 %), and sinusitis (3 %).

Warnings and Precautions:

Regular and scheduled medical check-ups are of the utmost importance to assess treatment progress and check whether the symptoms are improving or worsening. Be cautious of potential unwanted effects on the nose, such as bloody mucus, nasal sores, unexplained nosebleeds, or whistling sounds while breathing with this medication. Be aware of the possibility of thrush in the nose or throat, and look for any white patches or pain. Immediate medical attention is required for signs of a serious allergic reaction, like facial or throat swelling, breathing difficulties, or hives.

For children using this medication, monitoring their growth patterns is required. Long-term use or high doses may affect adrenal gland activity. Watch for symptoms such as darkened skin, diarrhea, dizziness, loss of appetite, depression, or a skin rash. Look for any vision changes during or after treatment, and consider an ophthalmologist examination.

Drug Interactions:

Ciclesonide may interact with certain products, such as Aldesleukin, oral corticosteroids (like Prednisone and Dexamethasone), and Mifepristone. Additionally, some medications may influence the elimination of ciclesonide from the body, potentially affecting how Ciclesonide functions. Such medications include certain Azole antifungals (for example, Ketoconazole), HIV protease inhibitors (for example, Nelfinavir), Ritonavir, and others.

Clinical Studies:

Several clinical trials have been conducted to assess Ciclesonide's effectiveness, safety, and tolerability in treating allergic rhinitis. These trials used double-blind, placebo-controlled, randomized methods and included patients with seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). The results consistently showed that intranasal Ciclesonide outperformed placebo in relieving nasal symptoms in SAR patients. Its low systemic exposure and favorable safety profile supported its continued clinical development. For SAR and PAR patients, the optimal dose of 200 μg once daily showed significant reductions in nasal symptoms and improved health-related quality of life. Ciclesonide was well-tolerated and effective in relieving nasal symptoms without producing significant local or systemic side effects. These findings confirmed the dose range-finding study and provided strong evidence for the efficacy and safety of Ciclesonide in managing allergic rhinitis.

Furthermore, studies have shown that, along with the demonstrated clinical effectiveness of Ciclesonide, it may possess a favorable therapeutic and safety profile compared to certain currently available inhaled corticosteroid (ICS) treatments. As a result, Ciclesonide can potentially enhance adherence rates and improve patient therapeutic outcomes.

Multiple studies have assessed ciclesonide's impact on HPAA (hypothalamic-pituitary-adrenal axis) function. In a controlled study with healthy volunteers, ciclesonide (640 μg/day) showed no disruption of cortisol production or circadian rhythm. Further short-term and long-term studies also confirmed ciclesonide's efficacy and reduced systemic activity. Its unique pharmacologic characteristics, including low systemic availability, rapid elimination, and low oral bioavailability, may contribute to its lack of significant effects on HPAA function.