Spiriva Respimat 2.5 microgram, solution for inhalation

The delivered dose is 2.5 microgram tiotropium per puff (2 puffs comprise one medicinal dose) and is equivalent to 3.124 microgram tiotropium bromide monohydrate.

The delivered dose is the dose which is available for the patient after passing the mouthpiece.

For a full list of excipients, see section 6.1.

Solution for inhalation

Clear, colourless, solution for inhalation

Tiotropium is indicated as a maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD).

The medicinal product is intended for inhalation use only. The cartridge can only be inserted and used in the Respimat inhaler (see 4.2).

Two puffs from the Respimat inhaler comprise one medicinal dose.

The recommended dose for adults is 5 microgram tiotropium given as two puffs from the Respimat inhaler once daily, at the same time of the day.

The recommended dose should not be exceeded.

Special Populations:

Geriatric patients can use tiotropium bromide at the recommended dose.

Renally impaired patients can use tiotropium bromide at the recommended dose. For patients with moderate to severe impairment (creatinine clearance 50 ml/min, see 4.4 and 5.2).

Hepatically impaired patients can use tiotropium bromide at the recommended dose (see 5.2).

Paediatric patients:

Spiriva Respimat is not recommended for use in children and adolescents below 18 years due to lack of data on safety and efficacy (see 5.1 and 5.2).

To ensure proper administration of the medicinal product, the patient should be shown how to use the inhaler by a physician or other health professionals.

Patient's instructions for use and handling

Spiriva Respimat inhaler and Spiriva Respimat cartridge

Inserting the cartridge and preparation for use

The following steps 1-6 are necessary before first use:

 To prepare the Spiriva Respimat inhaler for first-time use

Using the Spiriva Respimat inhaler

You will need to use this inhaler ONLY ONCE A DAY.

Each time you use it take TWO PUFFS.

 When to get a new Spiriva Respimat inhaler

 How to care for your inhaler

Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at least once a week.

Any minor discoloration in the mouthpiece does not affect your Spiriva Respimat inhaler performance.

If necessary, wipe the outside of your Spiriva Respimat inhaler with a damp cloth.

Spiriva Respimat is contraindicated in patients with hypersensitivity to tiotropium bromide, atropine or its derivatives, e.g. ipratropium or oxitropium or to any of the excipients (see 6.1).

Tiotropium bromide, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy.

Immediate hypersensitivity reactions may occur after administration of tiotropium bromide solution for inhalation.

Consistent with its anticholinergic activity, tiotropium bromide should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.

Inhaled medicines may cause inhalation-induced bronchospasm.

Spiriva Respimat should be used with caution in patients with known cardiac rhythm disorders (see 5.1).

As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance 50 ml/min) tiotropium bromide should be used only if the expected benefit outweighs the potential risk. There is no long term experience in patients with severe renal impairment (see 5.2).

Patients should be cautioned to avoid getting the spray into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these eye symptoms develop, patients should stop using tiotropium bromide and consult a specialist immediately.

Dry mouth, which has been observed with anti-cholinergic treatment, may in the long term be associated with dental caries.

Tiotropium bromide should not be used more frequently than once daily (see 4.9).

Although no formal drug interaction studies have been performed, tiotropium bromide has been used concomitantly with other drugs commonly used in the treatment of COPD, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids without clinical evidence of drug interactions.

The co-administration of tiotropium bromide with other anticholinergic containing drugs has not been studied and therefore is not recommended.

For tiotropium bromide, no clinical data on exposed pregnancies are available. Animal studies have shown reproductive toxicity associated with maternal toxicity (see 5.3).

The potential risk for humans is unknown. Spiriva Respimat should therefore only be used during pregnancy when clearly indicated.

It is unknown whether tiotropium bromide is excreted in human breast milk. Despite studies in rodents which have demonstrated that excretion of tiotropium bromide in breast milk occurs only in small amounts, use of Spiriva Respimat is not recommended during breast-feeding. Tiotropium bromide is a long-acting compound. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Spiriva Respimat should be made taking into account the benefit of breast-feeding to the child and the benefit of Spiriva Respimat therapy to the woman.

No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness or blurred vision may influence the ability to drive and use machinery.

a) General description

Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide.

b) Table of Undesirable effects according to the MedDRA terminology

The frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (2,802 patients) pooled from 5 placebo-controlled clinical trials with treatment periods ranging from twelve weeks to one year.

Frequency is defined using the following convention:

Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

* frequency not known, no adverse drug reaction observed in 2,802 patients

c) Information characterising individual serious and/or frequently occurring undesirable effects

In controlled clinical studies, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 3.2% of patients.

In 5 clinical trials, dry mouth led to discontinuation in 3 of 2,802 tiotropium treated patients (0.1 %).

Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention.

Additional information on special populations

An increase in anticholinergic effects may occur with increasing age.

High doses of tiotropium bromide may lead to anticholinergic signs and symptoms.

However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 340 microgram tiotropium bromide in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth/throat and dry nasal mucosa, were observed following 14-day dosing of up to 40 microgram tiotropium solution for inhalation in healthy volunteers with the exception of pronounced reduction in salivary flow from day 7 onwards. No significant undesirable effects have been observed in four long term-studies in COPD patients with a daily dose of 10 microgram tiotropium solution for inhalation over 4-48 weeks.

Acute intoxication by inadvertent oral ingestion of tiotropium solution for inhalation from the cartridge is unlikely due to low oral bioavailability.

Pharmacotherapeutic group: Anticholinergics

ATC code: R03B B04

Tiotropium bromide is a long-acting, specific antagonist at muscarinic receptors. It has similar affinity to the subtypes, M₁ to M₅. In the airways, tiotropium bromide competitively and reversibly binds to the M₃ receptors in the bronchial smooth musculature, antagonising the cholinergic (bronchoconstrictive) effects of acetylcholine, resulting in bronchial smooth muscle relaxation. The effect was dose dependent and lasted longer than 24h. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur.

The dissociation of tiotropium from especially M₃-receptors is very slow, exhibiting a significantly longer dissociation half-life than ipratropium. Dissociation from M₂-receptors is faster than from M₃, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M₃ over M₂. The high potency, very slow receptor dissociation and topical inhaled selectivity found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.

The clinical Phase III development programme included two 1-year, two 12-weeks and two 4-weeks randomised, double-blind studies in 2901 COPD patients (1038 receiving the 5 µg tiotropium dose). The 1-year programme consisted of two placebo-controlled trials. The two 12-week trials were both active (ipratropium) - and placebo-controlled. All six studies included lung function measurements. In addition, the two 1-year studies included health outcome measures of dyspnoea, health-related quality of life and effect on exacerbations.

In the aforementioned studies, tiotropium solution for inhalation, administered once daily, provided significant improvement in lung function (forced expiratory volume in one second and forced vital capacity) within 30 minutes following the first dose, compared to placebo (FEV₁ mean improvement at 30 minutes: 0.113 litres; 95% confidence interval (CI): 0.102 to 0.125 litres, p< 0.0001). Improvement of lung function was maintained for 24 hours at steady state compared to placebo (FEV₁ mean improvement: 0.122 litres; 95% CI: 0.106 to 0.138 litres, p< 0.0001).

Pharmacodynamic steady state was reached within one week.

Spiriva Respimat significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings compared to placebo (PEFR mean improvement: mean improvement in the morning 22 L/min; 95% CI: 18 to 55 L/min, p< 0.0001; evening 26 L/min; 95% CI: 23 to 30 L/min, p<0.0001). The use of Spiriva Respimat resulted in a reduction of rescue bronchodilator use compared to placebo (mean reduction in rescue use 0.66 occasions per day, 95% CI: 0.51 to 0.81 occasions per day, p<0.0001).

The bronchodilator effects of Spiriva Respimat were maintained throughout the 1-year period of administration with no evidence of tolerance.

The following health outcome effects were demonstrated in the long term 1-year studies:

(a) Spiriva Respimat significantly improved dyspnoea (as eva luated using the Transition Dyspnoea Index) compared to placebo (mean improvement 1.05 units; 95% CI: 0.73 to 1.38 units, p<0.0001). An improvement was maintained throughout the treatment period.

(b) The improvement in mean total score of patient's eva luation of their Quality of Life (as measured using the St. George's Respiratory Questionnaire) between Spiriva Respimat versus placebo at the end of the two 1-year studies was 3.5 units (95% CI: 2.1 to 4.9, p<0.0001). A 4-unit decrease is considered clinically relevant.

(c) COPD Exacerbations

In three one-year, randomised, double-blind, placebo-controlled clinical trials Spiriva Respimat treatment resulted in a significantly reduced risk of a COPD exacerbation in comparison to placebo. Exacerbations of COPD were defined as “a complex of at least two respiratory events/symptoms with a duration of three days or more requiring a change in treatment (prescription of antibiotics and/or systemic corticosteroids and/or a significant change of the prescribed respiratory medication)”. Spiriva Respimat treatment resulted in a reduced risk of a hospitalisation due to a COPD exacerbation (significant in the appropriately powered large exacerbation trial).

The pooled analysis of two Phase III trials and separate analysis of an additional exacerbation trial is displayed in Table 1. All respiratory medications except anticholinergics and long-acting beta-agonists were allowed as concomitant treatment, i.e. rapidly acting beta-agonists, inhaled corticosteroids and xanthines. Long-acting beta-agonists were allowed in addition in the exacerbation trial.

Table 1: Statistical Analysis of Exacerbations of COPD and Hospitalized COPD Exacerbations in Patients with Moderate to Very Severe COPD

^a Time to first event: days on treatment by when 25% of patients had at least one exacerbation of COPD / hospitalized COPD exacerbation. In study A 25% of placebo patients had an exacerbation by day 112, whereas for Spiriva Respimat 25% had an exacerbation by day 173 ( p=0.09);in study B 25% of placebo patients had an exacerbation by day 74, whereas for Spiriva Respimat 25% had an exacerbation by day 149 (p<0.0001).

^b Hazard ratios were estimated from a Cox proportional hazard model. The percentage risk reduction is 100(1 - hazard ratio).

^c Poisson regression. Risk reduction is 100(1 - rate ratio).

^d Pooling was specified when the studies were designed. The exacerbation endpoints were significantly improved in individual analyses of the two one year studies.

In a retrospective pooled analysis of the three 1-year and one 6-month placebo-controlled trials with Spiriva Respimat including 6,096 patients a numerical increase in all-cause mortality was seen in patients treated with Spiriva Respimat (68; incidence rate (IR) 2.64 cases per 100 patient-years) compared with placebo (51, IR 1.98) showing a rate ratio (95% confidence interval) of 1.33 (0.93, 1.92) for the planned treatment period; the excess in mortality was observed in patients with known rhythm disorders.

a) General Introduction

Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is available as solution for inhalation administered by the Respimat inhaler. Approximately 40% of the inhaled dose is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.

b) General Characteristics of the Active Substance after Administration of the Medicinal Product