Tiotropium inhalers

Generic Name

Tiotropium bromide

Brand Names

Spiriva HandiHaler

Spiriva Respimat

Braltus

Tiova

Tionair

Tazima

Tiotropium inhalers are available in both dry powder inhaler (DPI) and soft mist inhaler (SMI) formulations depending on the device

Drug Class

Long-acting muscarinic antagonist

Anticholinergic bronchodilator

Maintenance inhaler

Also referred to as a LAMA

Mechanism of Action

Tiotropium is a long-acting competitive antagonist at muscarinic M1 and M3 receptors located in the airway smooth muscle

It dissociates slowly from M3 receptors providing a prolonged duration of bronchodilation

M1 receptor inhibition reduces mucus secretion and M3 blockade inhibits bronchoconstriction leading to improved airflow

Its long duration of action supports once-daily dosing

It is functionally selective due to faster dissociation from M2 receptors compared to M1 and M3 receptors thereby minimizing inhibitory effects on the M2 autoreceptor

Bronchodilation results from inhibition of vagally mediated acetylcholine-induced airway constriction

Indications

Chronic obstructive pulmonary disease (COPD)

Maintenance treatment of bronchospasm associated with COPD including chronic bronchitis and emphysema

Reduction of COPD exacerbations

Asthma

Maintenance treatment of asthma in patients aged six years and older as add-on therapy to inhaled corticosteroids with or without long-acting beta agonists

Approved for asthma in moderate to severe cases not controlled by conventional ICS and LABA therapy

Dosage and Administration

Spiriva HandiHaler

DPI device containing 18 microgram capsules

Inhale contents of one capsule (18 micrograms) once daily using the HandiHaler device

Each capsule should be used immediately after removal from the blister

Do not swallow the capsule

Spiriva Respimat

SMI device delivering 2.5 micrograms per actuation

Two actuations (total dose 5 micrograms) inhaled once daily

For asthma the approved dose is also 2 puffs once daily

Priming is required before first use and if not used for more than three weeks

Braltus

DPI delivering 13 micrograms per inhalation

Usual dose is two inhalations of 13 micrograms once daily (total 26 micrograms)

Same pharmacokinetic target as Spiriva

Onset and duration

Onset of bronchodilation occurs within 30 minutes

Peak effect within 3 hours

Bronchodilation maintained for 24 hours allowing once-daily dosing

Pharmacokinetics

Absorption

Poor oral bioavailability

Systemic absorption occurs via pulmonary route

Approximately 19 percent of the dose from Respimat reaches systemic circulation

Distribution

Low plasma protein binding about 72 percent

High tissue affinity due to slow dissociation from muscarinic receptors

Metabolism

Extensively metabolized by nonenzymatic ester hydrolysis and minor CYP450 metabolism (mainly CYP2D6 and CYP3A4)

Elimination

Mainly renal excretion of unchanged drug

Approximately 75 percent excreted unchanged in urine

Terminal elimination half-life is about 25 to 44 hours

Prolonged in elderly and patients with renal impairment

Contraindications

Hypersensitivity to tiotropium or atropine and its derivatives

Hypersensitivity to milk proteins in dry powder formulations

Avoid in patients with known hypersensitivity reactions including angioedema or urticaria to prior use of LAMAs

Warnings and Precautions

Paradoxical bronchospasm

Rarely can occur after inhalation

If it happens discontinue immediately and consider alternative therapy

Urinary retention

May worsen urinary symptoms especially in patients with prostatic hyperplasia or bladder neck obstruction

Monitor for symptoms such as difficulty urinating or painful urination

Narrow-angle glaucoma

May increase intraocular pressure if sprayed into the eyes

Avoid ocular exposure

Advise patients to wash hands after handling and not to spray near eyes

Dry mouth and dental caries

Most common anticholinergic effect

Long-term use may contribute to oral discomfort or dental issues

CNS effects

Rare reports of dizziness or blurred vision

Use caution while driving or operating machinery

Use in acute bronchospasm

Not indicated for relief of acute bronchospasm or rescue therapy

Patients should have a separate rescue inhaler such as salbutamol

Adverse Effects

Very common

Dry mouth

Common

Constipation

Dysphonia

Cough

Dizziness

Blurred vision

Pharyngitis

Sinusitis

Urinary tract infection

Headache

Uncommon

Tachycardia

Palpitations

Atrial fibrillation

Rash

Insomnia

Nausea

Glaucoma

Urinary retention

Rare

Angioedema

Anaphylaxis

Bronchospasm

Paradoxical wheezing

Overdose

Symptoms include anticholinergic effects such as dry mouth tachycardia constipation blurred vision and urinary retention

Treatment is supportive

No specific antidote available

Monitor heart rate and urinary symptoms in significant overdose

Drug Interactions

Anticholinergic drugs

Avoid concurrent use with other LAMAs such as glycopyrronium or umeclidinium due to risk of additive side effects

Beta agonists

No pharmacodynamic antagonism but close monitoring is advised if using multiple bronchodilators to avoid cardiovascular effects

CYP inhibitors

Tiotropium is metabolized only to a minor extent via CYP450 so clinically significant interactions with CYP3A4 or CYP2D6 inhibitors are unlikely

Diuretics

Concurrent use may increase risk of urinary retention or electrolyte imbalance

Monitor closely in elderly

Use in Special Populations

Pregnancy

Category C

Use only if potential benefit outweighs risk

No adequate studies in pregnant women

Lactation

Unknown if tiotropium is excreted in breast milk

Caution is advised

Pediatrics

Approved for use in asthma in patients six years and older using Respimat

Not approved for COPD in children

Geriatrics

No dose adjustment required

Increased incidence of urinary side effects due to age-related changes

Renal impairment

Systemic exposure increases with decreasing renal function

Use caution in severe renal impairment and monitor for anticholinergic side effects

Hepatic impairment

No dose adjustment necessary

Minimal hepatic metabolism

Monitoring Parameters

Monitor for effectiveness in improving airflow and reducing exacerbations

Watch for symptoms of dry mouth blurred vision urinary retention or constipation

Monitor for signs of paradoxical bronchospasm after inhalation

In long-term use monitor renal function and intraocular pressure in patients at risk

Comparative Pharmacology

Tiotropium vs ipratropium

Tiotropium is long-acting with once-daily dosing whereas ipratropium is short-acting requiring multiple doses per day

Tiotropium vs aclidinium

Tiotropium is dosed once daily while aclidinium requires twice-daily administration

Tiotropium vs glycopyrronium

Both are LAMAs but tiotropium has a longer clinical history and is available for both COPD and asthma

Tiotropium vs umeclidinium

Umeclidinium is similar in efficacy but often used as part of fixed-dose combinations with other bronchodilators

Tiotropium vs salmeterol

Tiotropium is an anticholinergic while salmeterol is a LABA

They are often used together in combination therapy for COPD or asthma

Formulations Available

Spiriva HandiHaler

Capsule for inhalation containing 18 micrograms tiotropium

Spiriva Respimat

Soft mist inhaler delivering 2.5 micrograms per puff

Two inhalations provide 5 micrograms total daily dose

Braltus

Dry powder inhaler delivering 13 micrograms per actuation

Two puffs once daily provide 26 micrograms

Tiova

Generic formulation used in various markets with similar DPI device

Regulatory and Legal Status

Approved globally for maintenance therapy in COPD and asthma

Prescription-only medication

Included in national COPD and asthma guidelines as a maintenance bronchodilator

WHO Essential Medicines List includes tiotropium for symptomatic treatment of moderate to severe COPD