Tiotropium

Tiotropium belongs to the Anti-Cholinergics Pharmacological class.

Tiotropium has been approved for the treatment of Asthma, bronchospasm, COPD (Chronic Obstructive Pulmonary Disease), and asthma exacerbations.

A 33% of Tiotropium is absorbed after oral administration, which reaches the systemic circulation with low bioavailability of 2-3%. Tiotropium achieved a volume of distributions of 32 L/kg. Following the intravenously administered dose, about 74% of the dose is excreted in an unchanged form. The Tiotropium is found to be nonenzymatically cleaved to the inactive metabolites N-methylscopine and dithienylglycolic acid.

The common side effects associated with Tiotropium are dry mouth, constipation, upset stomach, vomiting, cold symptoms, nosebleed, and muscle pain.

Tiotropium is available in the form of Inhalation Powder and Inhalation Solution.

Tiotropium is available in India, U.K., U.S., Canada, India, E.U., China, Japan, and Australia.

Tiotropium belongs to the pharmacological class of Anticholinergics. Through its long action on Muscarinic receptors, Tiotropium appears to inhibit the muscarinic receptors, especially the M₃ receptor. This M₃ receptor hence acts on the bronchial smooth muscles in the lungs and leads to Bronchodilation.

Tiotropium has a quick onset of action and is found to be 30 minutes, and the duration of action is around 24 hrs that allows for once-a-day dosing.

Tiotropium plasma tiotropium concentrations were assayed with LLOQ of 0.1pg/mL was assayed and was found that the mean Cmax was found to be 4.98 ± 3.55pg/mL, and a median Tmax of 3.6 minutes was achieved.

Tiotropium is available in Inhalation Powder and Inhalation Solution

Inhalation Powder.

1. Each Spiriva capsule contains powder for Inhalation that shouldn’t be opened.
2. The dust cap is opened by pressing the green piercing button.
3. The dust cap is pulled upwards so as to expose the mouthpiece.
4. The mouthpiece is opened by pulling up the mouthpiece ridge so that the center chamber is visible.
5. The capsule is placed in the center chamber of the hand inhaler
6. The mouthpiece is firmly closed until a click sound is heard by leaving the dust cap open.
7. The mouthpiece is held upwards and the green piercing button is pressed and then released to make holes in the capsule.
8. It is not advised to press the green button more than one time.
9. Breathe out completely before you breathe in the medication from the inhaler and hold it for a few seconds.

Inhalation Solution

1. The cap is kept closed.
2. The clear base is removed and the safety catch is pressed while firmly pulling off the base with the other hand.
3. The cartridge is inserted into the haler.
4. The inhaler is placed on a firm surface until a clicking sound is heard.
5. The checkbox is marked on the inhaler label.
6. The clear base is put back until it is clicked.
7. Now the clear base is turned in the direction of arrows on the label until it clicks (half a turn).
8. The cap is fully opened.
9. The inhaler is pointed toward the ground, the dose-release button is pressed.
10. The cap is closed
11. Steps 7-10 are repeated until a cloud is visible.
12. Steps 7-10 are repeated three more times.
13. Now the inhaler is held upright with the cap closed.
14. The base is turned in the direction of arrows on the label until it clicks (half a turn).
15. The cap is opened fully.
16. Now breathe out gently away from the inhaler
17. The mouthpiece is put near the mouth and inhaled deeply at the same time releasing the dose-release button.
18. The breath is held for 5 seconds.
19. Now the inhaler is removed away from the mouth while keeping the inhaler intact.
20. Breathe out gently and close the cap.

Tiotropium can be used in the treatment of:

• Asthma
• Bronchospasm
• COPD(Chronic Obstructive Pulmonary Disease)
• Asthma exacerbations

Tiotropium can help to relieve symptoms of Asthma, bronchospasm, COPD (Chronic Obstructive Pulmonary Disease), and Asthma exacerbations.

Tiotropium is approved for use in the following clinical indications:

• Asthma
• Bronchospasm
• COPD(Chronic Obstructive Pulmonary Disease)
• Asthma exacerbations

• Chronic Obstructive Pulmonary Disease

Inhalation Powder: 2 PO inhalations of 1 capsule (18 mcg) via HandiHaler inhalation device

Solution Inhalation: 5 mcg (2 actuation; 2.5 mcg/actuation) inhaled.

• Asthma

Tiotropium is indicated for long-term, once-daily, maintenance treatment of asthma in patients aged ≥12 yr.

Solution Inhalation: 2.5 mcg (2 actuations; 1.25 mcg/actuation)

Inhalation Powder: 18mcg,

Solution Inhalation: 1.25 mcg, 2.5mcg

Inhalation Powder: 18mcg,

Solution Inhalation: 1.25 mcg, 2.5mcg

Dosage Adjustments in Kidney Patients:

• In patients with Mild renal dysfunction (CrCl 60 mL/min or more), no adjustment is recommended.

• In patients with Moderate to Severe renal dysfunction (CrCl less than 60 mL/min), it is advised to use Tiotropium with caution.

Smoking cessation and maintaining health are a must.

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

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 are needed to be individualized as per the patient's requirements.

Tiotropium may be contraindicated during the co-administration with the following drugs:

• Hypersensitivity to the ingredients of the medication
• Hypersensitivity to Atropine and other related derivatives

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

Not for Acute Use

Tiotropium is found to be intended as a once-a-day maintenance treatment for asthma and COPD and it should not be used for the relief of acute symptoms, such as rescue therapy for the treatment of acute episodes of bronchospasm.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions such as urticaria, angioedema, rashes, bronchospasm, anaphylaxis, or itching may occur after the administration of Tiotropium. The therapy with Tiotropium should be stopped at once and alternative treatments should be considered when such a reaction occurs. Atropine and Tiotropium have a similar structural formula, therefore it is advised that patients with a history of hypersensitivity effects to atropine or its derivatives should be closely monitored if similar hypersensitivity reactions to that of Tiotropium are noted.

Paradoxical Bronchospasm

Inhaled medications, including Tiotropium, might lead to paradoxical bronchospasm. In such conditions, it should be treated immediately with an inhaled short-acting beta2-agonist such as albuterol. Treatment with Tiotropium should be withdrawn immediately and other treatments considered.

Worsening of Narrow-Angle Glaucoma

Tiotropium should be administered with caution in patients suffering from narrow-angle glaucoma. It is advised that prescribers and patients should be alert for signs of acute narrow-angle glaucoma such as eye pain or discomfort, blurred vision, etc. It is advised that the Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.

Worsening of Urinary Retention

Tiotropium should be administered with caution in patients suffering from urinary retention. Physicians and patients should be alert for signs and symptoms of urinary retention such as difficulty passing urine, and painful urination, especially in patients suffering from prostatic hyperplasia or bladder-neck obstruction. It is advised that the patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.

Renal Impairment

As a predominantly really excreted drug, patients with moderate to severe renal impairment (creatinine clearance of less than 60 mL/min) treated with Tiotropium should be monitored closely for anticholinergic side effects

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

Clinical data related to Breastfeeding woman being exposed to Tiotropium are not available. Based on studeis on the lactating rodent, Tiotropium is found to be excreted into breast milk.Therefore, caution should be excerscised.

Pregnancy Category C.

There was found to be no adequate and well-controlled studies in pregnant women. Tiotropium should be used only during pregnancy only if the potential benefits outweighs the potential risks associated with the fetus. No evidence of structural alterations were observed in rats and rabbits at approximately 790 and 8 times the maximum recommended human daily inhalation dose, respectively. However, in rats, it was observed that Tiotropium caused effects such as fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at inhalation doses tiotropium of approximately 40 times the MRHDID. In rabbits, Tiotropium caused an increase in post implantation loss at an inhalation dose of approximately 430 times the MRHDID. Such effects had not been observed at approximately 5 and 95 times the MRHDID, respectively.

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

The adverse reactions related to Tiotropium can be categorized as:

Common

• Dry Mouth
• Headache
• Cough
• Throat Irritation
• Inflammation Of The Tissue Lining The Sinuses
• Bronchitis

Less common

• Dizziness
• A Change In Voice
• Heart Throbbing Or Pounding
• Vomiting Ear congestion
• Thrush
• A Stuffy And Runny Nose
• Gastroesophageal Reflux Disease
• Constipation
• Itching
• Arthritis

Rare

• Paroxysmal Supraventricular Tachycardia
• Atrial Fibrillation
• Blocked Bowels With Decreased Peristaltic Movement
• Abnormal Liver Function Tests
• A Type Of Allergic Reaction Called Angioedema
• A Hypersensitivity Reaction To A Drug
• Increased Pressure In The Eye
• Glaucoma, An Increased Pressure In The Eye
• Worsening Of Glaucoma
• High Blood Pressure
• Angina, A Type Of Chest Pain

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

An interaction study with Tiotropium of about 14.4 mcg intravenous infusion over 15 minutes and

cimetidine of about 400 mg thrice daily or ranitidine 300 mg once a day had been conducted

The co-administration of cimetidine with tiotropium resulted in around 20% increase in the AUC0–4h, a 28% decrease in the renal clearance of Tiotropium and there was found to be no significant change in the Cmax and amount of drug excreted in urine over 96 hours. Co-administration of Tiotropium with ranitidine did not affect the pharmacokinetics of Tiotropium. Hence, no clinically significant interaction occurred between Tiotropium and cimetidine or ranitidine.

The common side effects of Tiotropium include the following:

• Dry mouth
• Constipation
• Upset stomach
• Vomiting
• Cold symptoms
• Nosebleed
• Muscle pain.

Pregnancy

Teratogenic Effects:

There was found to be no adequate and well-controlled studies in pregnant women. Tiotropium should be used only during pregnancy only if the potential benefits outweighs the potential risks associated with the fetus. No evidence of structural alterations were observed in rats and rabbits at approximately 790 and 8 times the maximum recommended human daily inhalation dose in adults, respectively. However, in rats, it was observed that Tiotropium caused effects sucg s decreases in the number of live pups at birth and the mean pup weights, fetal resorption, litter loss, and a delay in pup sexual maturation at inhalation doses tiotropium of approximately 40 times the MRHDID. In rabbits, Tiotropium caused an increase in post implantation loss at an inhalation dose of approximately 430 times the MRHDID. Such effects had not been observed at approximately 5 and 95 times the MRHDID, respectively.

Nursing Mothers

Clinical data related to Breastfeeding woman being exposed to Tiotropium are not available. Based on studies on the lactating rodent, Tiotropium is found to be excreted into breast milk. Therefore, caution should be exercised.

Pediatric Use

The safety and efficacy of Tiotropium 2.5 mcg have been established in adolescents (aged 12 to 17 years) with asthma in 3 clinical trials up to 1 year in duration. In the 3 clinical trials, 327 patients aged 12 to 17 years with asthma were treated with Tiotropium 2.5 mcg. Patients in this age group demonstrated efficacy results similar to those observed in patients aged 18 years and older with asthma. The adverse drug reactions profile for this age group was comparable to that observed for patients aged 18 years and older with asthma. Based on available data, no adjustment of dosage of Tiotropium in adolescent patients with asthma is warranted. The safety and efficacy of Tiotropum have not been established in pediatric patients less than 12 years of age

Geriatric Use

Based on available data, no dosage adjustment of Tiotropium in geriatric patients is warranted. No overall differences in effectiveness have been observed among these group of people.

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

High doses of Tiotropium might lead to anticholinergic signs and symptoms. However, there were found to be no systemic anticholinergic adverse effects following a single inhaled dose of oof about 282 mcg tiotropium in 6 healthy volunteers. In a study which included 12 healthy volunteers, bilateral conjunctivitis and dry mouth were observed followed by repeated once a day inhalation of 141 mcg of Tiotropium.

Treatment of overdosage included discontinuation of Tiotropium together with institution of appropriate symptomatic and/or supportive therapy.

Pharmacodynamics

• Cardiovascular Effects

In a multicenter, randomized, double-blind trial that enrolled around 198 patients with Chronic Obstructive Pulmonary Disease, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the Tiotropium group when compared with placebo. This difference was apparent using both the Bazett (QTcB) [(20%) patients vs (12%) patients] and Fredericia (QTcF) [(16%) patients vs (1%) patient] corrections of QT for heart rate. None of the patients in either group had either QTcB or QTcF of >500 msec. Other clinical studies with Tiotropium did not detect an effect of the drug on QTc intervals.

The effect of Tiotropium on QT interval was also evaluated in a randomized, placebo, and positive-controlled crossover study in 53 healthy volunteers. Subjects had received Tiotropium 18 mcg, 54 mcg which is about 3 times the recommended dose, or placebo for around 12 days. ECG assessments were performed at baseline and throughout the dosing interval which was followed by the first and last dose of study medication. The maximum mean change from baseline relative to the placebo in study-specific QTc interval was found to be 3.2 msec and 0.8 msec for Tiotropium 18 mcg and 54 mcg, respectively. None of the subjects showed a new onset of QTc >500 msec or QTc changes from a baseline of ≥60 msec.

Pharmacokinetics

• Absorption

Followed by the dry powder inhalation in young healthy volunteers, the absolute bioavailability was found to be 19.5% which suggests that the fraction of the drug reaching the lung is found to be highly bioavailable. It is expected that from the chemical structure of the compound which is a quaternary ammonium compound the drug Tiotropium is poorly absorbed by the gastrointestinal tract. The effect of food on the bioavailability of Tiotropium has not been studied. Oral solutions of Tiotropium have been found to have an absolute bioavailability of 2% to 3%. Maximum plasma concentrations were observed 5 minutes after inhalation.

• Distribution

Tiotropium showed a volume of distribution of about 32 L/kg, indicating that the drug binds extensively to tissues. The human plasma protein binding for Tiotropium was found to be about 72%. At a steady state, peak tiotropium plasma levels in COPD patients were found to be 17 to 19 pg/mL when measured after 5 minutes of dry powder inhalation of an 18 mcg dose and a decrease in a multi-compartmental manner. Steady-state trough plasma concentrations were found to be 3 to 4 pg/mL. Local concentrations in the lung have not been found, but the mode of administration suggests substantially higher concentrations in the lung. Animal studies have shown that Tiotropium does not readily penetrate the blood-brain barrier.

• Metabolism

The extent of metabolism seems to be small. This is evident from the fact of the urinary excretion of 74% of the unchanged drug after an intravenous dosage to young and healthy volunteers. Tiotropium, which is an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid. Neither of them binds to muscarinic receptors. The in vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose which is 74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism, which is found to be metabolized by the enzyme cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites.

• Elimination

The elimination half-life of Tiotropium the following inhalation was found to be between 5 and 6 days. Total clearance was found to be about 880 mL/min after an intravenous dose in young healthy volunteers with an inter-individual variability of 22%. Intravenously administered Tiotropium was found to be mainly excreted unchanged in urine which was about 74%. After dry powder inhalation, urinary excretion was found to be about 14% of the dose, the remainder as being mainly a non-absorbed form of the drug in the gut which was found to be eliminated via the feces. The renal clearance of Tiotropium seems to exceed the creatinine clearance, indicating the active secretion into the urine. After chronic once-in-a-day inhalation by COPD patients, a pharmacokinetic steady state was reached after 2 to 3 weeks with no accumulation thereafter.

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