ciclesonide/formoterol/tiotropium

Action and Spectrum

Actions and Spectrum: 

Action:  

ciclesonide is an inhaled corticosteroid (ICS). It exerts its action by reducing inflammation in the airways. When inhaled, ciclesonide is activated by lung enzymes to form an active metabolite called des-ciclesonide, which binds to glucocorticoid receptors in the airway cells. This binding suppresses various inflammatory mediators, reducing swelling and mucus production and making the airways less sensitive to triggers. 

formoterol is a long-acting beta2-adrenergic agonist (LABA). It generally works by relaxing the smooth muscles of the airways, which helps to open up the air passages and improve breathing. formoterol acts rapidly, and its effects last about 12 hours, making it suitable for maintenance and reliever therapy. 

tiotropium is a long-acting muscarinic antagonist (LAMA). It generally works by blocking the action of acetylcholine, a neurotransmitter responsible for causing smooth muscle constriction. By doing so, tiotropium helps to relax the smooth muscles around the airways, leading to bronchodilation and improved airflow. 

Spectrum:  

ciclesonide is primarily used for the maintenance treatment of asthma in adults and children of age >6 years. It helps prevent asthma attacks and control symptoms when used regularly. It may also be used to manage other respiratory conditions involving airway inflammation. 

formoterol is used in the treatment of asthma and COPD. Combined with an inhaled corticosteroid like ciclesonide, it forms a combination therapy that provides anti-inflammatory and bronchodilator effects. This combination is often used for patients who require both maintenance and quick relief of their symptoms. 

tiotropium is mainly used to manage COPD, including chronic bronchitis and emphysema. It is not typically used as a first-line treatment for asthma but may be considered in some instances where asthma is difficult to control or when asthma and COPD coexist. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Enhanced heart rate 

Sore throat, hoarse voice 

Vomiting 

Musculoskeletal pain 

Nausea 

Upper respiratory tract infection 

Headache 

Shaking or trembling 

Increased intraocular pressure 

Flu, cough 

Fungal infection in the mouth 

Black Box Warning

Black Box Warning: 

• ciclesonide/formoterol/tiotropium might relate to potential risks associated with corticosteroid use, such as an increased risk of asthma-related death or worsening asthma symptoms. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

ciclesonide: 

• Hypersensitivity: ciclesonide is contraindicated in individuals with known hypersensitivity or allergy to ciclesonide or any other components of the inhalation device. 

formoterol: 

• Hypersensitivity: formoterol is contraindicated in individuals with known hypersensitivity or allergy to formoterol or any other components of the inhalation device. 

tiotropium: 

• Hypersensitivity: tiotropium is contraindicated in individuals with known hypersensitivity or allergy to tiotropium or any other components of the inhalation device. 

Caution 

ciclesonide: 

• Systemic Effects of Corticosteroids: ciclesonide is an inhaled corticosteroid (ICS). When used at high doses for prolonged periods, systemic corticosteroid effects are possible, such as adrenal suppression, osteoporosis, cataracts, and impaired growth in children. To minimize these risks, the lowest effective dose of ciclesonide should be used, and a healthcare professional should regularly review the therapy. 
• Infections: Corticosteroids like ciclesonide can increase the risk of respiratory infections, including pneumonia and opportunistic infections. Caution should be exercised when using ciclesonide in patients with a history of tuberculosis or other chronic infections. 
• Immunosuppression: Corticosteroids have immunosuppressive effects, which may delay wound healing and also enhance the risk of infections. Patients should be cautious about exposure to contagious illnesses while using ciclesonide. 

formoterol: 

• Asthma-related Deaths: formoterol should not be used as monotherapy for asthma. It should always be combined with an inhaled corticosteroid for asthma management. Long-acting beta2-agonists (LABAs) like formoterol have been associated with an increased risk of asthma-related deaths in some patients. 
• Cardiovascular Effects: LABAs, including formoterol, can cause cardiovascular effects such as increased heart rate, blood pressure, and arrhythmias. Caution is required in patients with pre-existing cardiovascular conditions. 
• Hypersensitivity Reactions: formoterol can cause hypersensitivity reactions, including anaphylaxis. If any signs of allergic reactions occur (e.g., rash, swelling, difficulty breathing), immediate medical attention should be sought. 

tiotropium: 

• Acute Bronchospasm: tiotropium is not intended to relieve acute bronchospasm. It should not be used as a rescue medication. Short-acting bronchodilators should be used for immediate relief of bronchospasm. 
• Narrow-angle Glaucoma: tiotropium can cause eye-related side effects, and caution should be exercised in patients with narrow-angle glaucoma or a history of intraocular pressure elevation. 
• Urinary Retention: tiotropium may worsen urinary retention in patients with a history of bladder neck obstruction or benign prostatic hyperplasia (BPH). 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk: Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

ciclesonide is an inhaled corticosteroid (ICS) metabolized in the lungs to its active form, des-ciclesonide, which binds to glucocorticoid receptors, reducing airway inflammation and hypersensitivity. formoterol is a long-acting beta2-adrenergic agonist (LABA) that relaxes the smooth muscles of the airways, causing to bronchodilation and improved airflow.

tiotropium is a long-acting muscarinic antagonist that blocks the action of acetylcholine, resulting in bronchodilation and decreased airway constriction. ciclesonide/formoterol/tiotropium provides a comprehensive approach to managing respiratory conditions like asthma and chronic obstructive pulmonary disease (COPD) by addressing inflammation, bronchoconstriction, and airway hypersensitivity. 

Pharmacodynamics: 

Mechanism of action: 

ciclesonide is an inhaled corticosteroid that exerts its effects generally by binding to glucocorticoid receptors in the airway cells. It acts as a potent anti-inflammatory agent when activated to its active metabolite, des-ciclesonide. This binding leads to the suppression of various inflammatory mediators and reduces the synthesis of pro-inflammatory substances. Consequently, ciclesonide decreases airway inflammation, swelling, and mucus production, making the airways less sensitive to triggers and helping to prevent asthma attacks when used regularly. 

formoterol is a long-acting beta2-adrenergic agonist that acts as a bronchodilator. When inhaled, formoterol selectively binds to beta2-adrenergic receptors in smooth muscle cells of the airways. This binding activates the receptors, leading to the relaxation of the smooth muscles. As a result, the airways widen, allowing for increased airflow, decreased airway resistance, and improved breathing. formoterol provides rapid relief of bronchoconstriction and helps maintain bronchodilation over an extended period (up to 12 hours). 

tiotropium is a long-acting muscarinic antagonist that acts as a bronchodilator. It blocks the action of acetylcholine, a neurotransmitter that causes smooth muscle constriction in the airways. By competitively inhibiting muscarinic receptors in the airway smooth muscle, tiotropium prevents acetylcholine binding. This results in smooth muscle relaxation and bronchodilation, improving airflow and decreased airway resistance. tiotropium’s effects last for an extended duration, typically up to 24 hours, making it suitable for once-daily dosing in managing respiratory conditions like COPD. 

Pharmacokinetics: 

Absorption 

ciclesonide is administered via inhalation, which allows the drug typically to be delivered directly to the airways. After inhalation, ciclesonide is activated by esterases in the lungs to form its active metabolite, des-ciclesonide. 

formoterol is also administered via inhalation, allowing rapid absorption into the bloodstream. The onset of action is quick, making it suitable for rapid bronchodilation. 

tiotropium is delivered via inhalation and is rapidly absorbed from the lungs into systemic circulation, reaching its target receptors in the airway smooth muscles. 

Distribution 

ciclesonide and its active metabolite are distributed locally in the airway tissues, where they exert their anti-inflammatory effects. 

formoterol is distributed throughout the body and reaches the smooth muscle cells of airways, where it exerts its bronchodilatory effects. 

tiotropium is distributed primarily to the lung tissue and bronchial smooth muscles, where it exerts its bronchodilatory effects. 

Metabolism 

ciclesonide is primarily metabolized in the lungs to des-ciclesonide, the active form responsible for its anti-inflammatory actions. The metabolism of ciclesonide occurs mainly in the lung tissue and not significantly in the liver. 

formoterol undergoes hepatic metabolism (primarily by conjugation) to form inactive metabolites. 

tiotropium undergoes limited metabolism in the liver, and most of the drug is excreted unchanged. 

Elimination and Excretion 

ciclesonide and its metabolites are excreted from the body mainly via feces and, to a lesser extent, through urine. 

Most formoterol and its metabolites are excreted in the urine, with a smaller portion eliminated in the feces. 

tiotropium is primarily excreted unchanged in the feces, with a smaller amount eliminated in the urine. 

Adminstartion

Administration: 

Transhaler/Inhaler: 

Ensure proper mixing of the inhaler contents by shaking it thoroughly and reviewing the instructions on the label before administration. Inhale the medication through your mouth and press down on the inhaler one time to release the drug, then hold your breath for 10 seconds. Continue this process until you have taken the recommended number of puffs as your doctor prescribes.  

Transcaps/Rotacaps: 

The medication comes in the form of a powdered capsule designed for inhalation purposes only. Do not ingest the capsule. To administer, position the capsule at the base of the rotahaler/transhaler, a plastic inhalation device. Twist the mouthpiece entirely until you hear a clicking sound, indicating proper placement. Inhale deeply through the mouthpiece, holding your breath for 10 seconds. Afterward, remove the device and exhale normally. 

Transpules /Respules: 

A Transpule/Respule is a compact plastic container holding a liquid solution. To use it, unscrew the top of the Transpule/Respule and gently press to release the solution into the nebulizer. The nebulizer then converts this solution into a fine mist you can inhale. Breathe in the medicine through the nebulizer’s mouthpiece to receive the intended benefits. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ciclesonide/formoterol/tiotropium 

Why do we use ciclesonide/formoterol/tiotropium? 

formoterol (long-acting beta-agonists or bronchodilators), tiotropium (anticholinergic), and ciclesonide (corticosteroids) constitute the treatment regimen. tiotropium acts as an anticholinergic, while formoterol serves as a bronchodilator. Both medications relax the airway muscles, thereby widening the air passages.

The combined effect of these drugs facilitates improved breathing for individuals suffering from asthma and COPD. In contrast, ciclesonide functions as a corticosteroid, inhibiting the release of specific natural substances in the body that trigger airway inflammation.