CICLOFORM 160 INHALER

Indications

• Asthma maintenance therapy
• Chronic obstructive pulmonary disease (COPD)

Dosage

Children: For children aged 12–17 years: 160 micrograms once daily, reduced to 80 micrograms once daily if control is maintained; may increase if necessary up to 320 micrograms twice daily.

Adults: 160 micrograms once daily, reduced to 80 micrograms once daily if control is maintained; may increase to 320 micrograms twice daily if necessary.

Mechanism of action

Ciclesonide is a pro-drug that is converted into its active metabolite, des-ciclesonide, which binds to glucocorticoid receptors. This receptor-ligand complex translocates to the nucleus, where it interacts with glucocorticoid response elements in the DNA, leading to altered gene expression. This results in the suppression of pro-inflammatory cytokines such as IL-2, reduced synthesis of inflammatory mediators like prostaglandins and leukotrienes, and decreased infiltration of inflammatory cells in the airways.

Pharmacodynamics

As a glucocorticoid, ciclesonide exhibits potent anti-inflammatory properties. The active metabolite, des-ciclesonide, has a significantly higher affinity for glucocorticoid receptors than the parent compound, enhancing its efficacy. Ciclesonide affects various immune cell types, including eosinophils and mast cells, thereby reducing inflammatory responses in asthma and allergic conditions.

Pharmacokinetics

Ciclesonide undergoes extensive first-pass metabolism, resulting in a low systemic bioavailability. The active metabolite, des-ciclesonide, is responsible for its therapeutic effects. The drug is primarily eliminated via hepatic metabolism. The onset of action occurs within a few hours, but optimal effects may take several days of consistent use. Peak plasma concentrations are typically reached shortly after inhalation.

Contra-indications

• Hypersensitivity to ciclesonide or any of its components
• Untreated systemic fungal infections
• Untreated tuberculosis

Adverse effects

• Oral thrush
• Dysphonia
• Cough
• Headache
• Nausea
• Respiratory tract infection
• Cushing's syndrome (with high doses)
• Adrenal suppression

Interactions

• Cobicistat increases exposure to ciclesonide (unknown mechanism)
• Idelalisib increases exposure to ciclesonide (unknown mechanism)
• Clarithromycin increases exposure to ciclesonide (unknown mechanism)

Precautions

• Use with caution in patients with a history of serious mental health issues
• May cause hypercorticism or adrenal suppression at high doses or prolonged use
• Patients should be monitored for signs of infection
• Consider potential drug interactions with other corticosteroids or medications affecting the CYP3A4 pathway

Pregnancy

Ciclesonide is a Category C medication. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Ciclesonide is excreted in breast milk; caution is advised when administered to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Do not freeze.

Formulations

• {'name': 'Pressurised inhalation', 'dosage': '160 micrograms per dose', 'packaging': '60 doses'}
• {'name': 'Pressurised inhalation', 'dosage': '80 micrograms per dose', 'packaging': '120 doses'}
• {'name': 'Pressurised inhalation', 'dosage': '320 micrograms per dose', 'packaging': '120 doses'}

Indications

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Exercise-induced bronchospasm

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing guidelines, which may vary based on the child's age, weight, and the condition being treated.

Adults: Refer to the BNF for specific adult dosing guidelines, typically based on the severity of the condition and individual patient response.

Mechanism of action

Formoterol binds to and activates beta-2 adrenergic receptors on the smooth muscle cells of the airways. This activation leads to the stimulation of adenylate cyclase, increasing cyclic AMP levels. Elevated cyclic AMP results in the relaxation of bronchial smooth muscle and bronchodilation. Additionally, formoterol may exhibit anti-inflammatory effects by inhibiting the release of inflammatory mediators.

Pharmacodynamics

The pharmacodynamic effects of formoterol include bronchodilation, which is achieved through the relaxation of airway smooth muscle. The onset of action is typically within 1-3 minutes, with effects lasting up to 12 hours, allowing for twice-daily dosing. Formoterol also has a dose-dependent effect, where increased doses can lead to greater bronchodilation, but careful monitoring is required to avoid potential side effects like tachycardia or tremors.

Pharmacokinetics

Formoterol is well absorbed after inhalation, with peak plasma concentrations occurring approximately 30-60 minutes after administration. It is highly lipophilic, which allows for prolonged retention in lung tissue. The drug is metabolized primarily in the liver via the cytochrome P450 system, particularly CYP2D6. The elimination half-life is approximately 10 hours, facilitating its use as a long-acting bronchodilator.

Contra-indications

• Hypersensitivity to formoterol or any of its components
• Severe asthma exacerbation
• Cardiac arrhythmias
• Severe coronary artery disease

Adverse effects

• Tachycardia
• Palpitations
• Tremor
• Headache
• Dizziness
• Nausea
• Hypokalemia
• Hyperglycemia

Interactions

• Concomitant use with non-selective beta-blockers may reduce the effectiveness of formoterol
• Caution with other sympathomimetic agents as they may potentiate cardiovascular effects
• Corticosteroids may enhance the effect of formoterol

Precautions

• Monitor patients with cardiovascular disorders
• Use caution in patients with diabetes mellitus due to potential hyperglycemia
• May cause paradoxical bronchospasm; if this occurs, discontinue use immediately
• Assess lung function regularly during treatment

Pregnancy

Formoterol should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Consultation with a healthcare provider is recommended.

Breast-feeding

Formoterol is excreted in breast milk; however, the effects on the nursing infant are not well studied. Caution is advised.

Storage

Store in a cool, dry place, away from direct light. Do not freeze. Keep out of reach of children.

Formulations

• Inhalation aerosol
• Inhalation powder
• Nebulizer solution

Mechanism of action

Glucocorticoids such as ciclesonide can inhibit leukocyte infiltration at the site of inflammation, interfere with mediators of inflammatory response, and suppress humoral immune responses. The antiinflammatory actions of glucocorticoids are thought to involve phospholipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. Ciclesonide reduces inflammatory reaction by limiting the capillary dilatation and permeability of the vascular structures. These compounds restrict the accumulation of polymorphonuclear leukocytes and macrophages and reduce the release of vasoactive kinins. Recent research suggests that corticosteroids may inhibit the release of arachidonic acid from phospholipids, thereby reducing the formation of prostaglandins. Ciclesonide is a glucocorticoid receptor agonist. On binding, the corticoreceptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing an increase or decrease in expression of specific target genes, including suppression of IL2 (interleukin 2) expression.

Pharmacodynamics

Ciclesonide is a pro-drug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following intranasal application. Des-ciclesonide has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120 times higher than the parent compound. The precise mechanism through which ciclesonide affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic inflammation.