Spiriva Respimat

Tiotropium bromide.

The delivered dose is 2.5 µg tiotropium per puff (2 puffs per dose).
2.5 µg tiotropium is equivalent to 3.124 µg tiotropium bromide monohydrate (INN= tiotropium bromide).
Excipients/Inactive Ingredients: benzalkonium chloride, disodium edetate, purified water, hydrochloric acid for pH adjustment.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergics. ATC code: R03B B04.
Pharmacology: Tiotropium bromide is a long-acting, specific antimuscarinic agent, in clinical medicine often called an anticholinergic. It has a similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, inhibition of M3-receptors at the smooth muscle results in relaxation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In non-clinical in vitro as well as in vivo studies bronchoprotective effects were dose-dependent and lasted longer than 24 hours. The long duration of effect is likely to be due to its very slow dissociation from M3-receptors, exhibiting a significantly longer dissociation half-life than that seen with ipratropium. As an N-quaternary anticholinergic tiotropium is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before giving rise to systemic anti-cholinergic effects. 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 and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD and asthma. The bronchodilation following inhalation of tiotropium is primarily a local effect (on the airways) not a systemic one.
COPD: The clinical Phase III programme for COPD 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.
Placebo-controlled studies: Lung function: SPIRIVA RESPIMAT, 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. Improvement of lung function was maintained for 24 hours at steady state. 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. The use of SPIRIVA RESPIMAT resulted in a reduction of rescue bronchodilator use compared to placebo.
The bronchodilator effects of SPIRIVA RESPIMAT were maintained throughout the 48-week period of administration with no evidence of tolerance. (See Figure 1, Figure 2 and Figure 3.)


Click on icon to see table/diagram/image




Click on icon to see table/diagram/image




Click on icon to see table/diagram/image


A combined analysis of two randomised, placebo-controlled, crossover, clinical studies demonstrated that the bronchodilator response for SPIRIVA RESPIMAT (5 μg) was numerically higher compared to SPIRIVA HandiHaler (18 μg) inhalation powder after a 4-week treatment period.
Dyspnoea, Health-related Quality of Life, COPD Exacerbations in long-term 1 year studies: SPIRIVA RESPIMAT significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index). An improvement was maintained throughout the treatment period.
Patients' evaluation of their Quality of Life (as measured using the St. George's Respiratory Questionnaire) showed that SPIRIVA RESPIMAT had positive effects on the psychosocial impacts of COPD, activities affected by COPD and distress due to COPD symptoms.
The improvement in mean total score between SPIRIVA RESPIMAT versus placebo at the end of the two 1-year studies was statistically significant and maintained throughout the treatment period.
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 the table as follows. 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. (See table).


Click on icon to see table/diagram/image


Long-term tiotropium active - controlled study: A long term, large scale, randomised, double-blind, active-controlled study with a treatment period up to 3 years has been performed to compare the efficacy and safety of SPIRIVA RESPIMAT and SPIRIVA HANDIHALER (5,711 patients receiving SPIRIVA RESPIMAT 2.5 microgram (5 microgram medicinal dose); 5,694 patients receiving SPIRIVA HANDIHALER). The primary endpoints were time to first COPD exacerbation, time to all-cause mortality and in a sub-study (906 patients) trough FEV₁ (pre-dose).
The time to first COPD exacerbation was similar during the study with SPIRIVA RESPIMAT and SPIRIVA HANDIHALER (hazard ratio (SPIRIVA RESPIMAT / SPIRIVA HANDIHALER) 0.98 with a 95% CI of 0.93 to 1.03).
The median number of days to the first COPD exacerbation was 756 days for SPIRIVA RESPIMAT and 719 days for SPIRIVA HANDIHALER.
The bronchodilator effect of SPIRIVA RESPIMAT was sustained over 120 weeks, and was similar to SPIRIVA HANDIHALER. The mean difference in trough FEV₁ for SPIRIVA RESPIMAT versus SPIRIVA HANDIHALER was -0.010 L (95% CI -0.038 to 0.018 mL).
All-cause mortality was similar during the study with SPIRIVA RESPIMAT and SPIRIVA HANDIHALER (hazard ratio (SPIRIVA RESPIMAT / SPIRIVA HANDIHALER) 0.96 with a 95% CI of 0.84 to 1.09).
Asthma: The clinical Phase III programme for persistent asthma included two 1-year, randomised, double-blind, placebo-controlled studies in a total of 907 asthma patients (453 receiving SPIRIVA RESPIMAT) on a combination of ICS with a LABA.
In the two 1-year PrimoTinA-asthma studies in patients who were symptomatic on maintenance treatment of at least high-dose ICS plus LABA, SPIRIVA RESPIMAT showed significant improvements in lung function (FEV₁) over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV₁ were 0.110 litres (95% CI: 0.063 to 0.158 litres, p<0.0001) and 0.093 litres (95% CI: 0.050 to 0.137 litres, p<0.0001), respectively.
The improvement of lung function compared to placebo was maintained for 24 hours (see Figure 4).


Click on icon to see table/diagram/image


At week 24, SPIRIVA RESPIMAT significantly improved morning and evening peak expiratory flow (PEF); mean improvement in the morning 23 L/min; 95% CI: 16 to 29 L/min, p< 0.0001; evening 26 L/min; 95% CI: 20 to 33 L/min, p<0.0001.
The bronchodilator effects of SPIRIVA RESPIMAT were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis or tolerance. (See Figure 5).


Click on icon to see table/diagram/image


Pharmacokinetics: Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is available as inhalation 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 as recommended for therapy.
Absorption: Following inhalation by young healthy volunteers, urinary excretion data suggest that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of tiotropium for the same reason. Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation. At steady state, peak tiotropium plasma concentrations of 10.5 pg/mL were achieved in COPD patients and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.60 pg/mL.
A steady-state tiotropium peak plasma concentration of 5.15 pg/mL was attained 5 minutes after the administration of the same dose to patients with asthma.
Distribution: The drug has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg.
Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium bromide does not penetrate the blood-brain barrier to any relevant extent.
Biotransformation: The extent of biotransformation is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium bromide, an ester, is nonenzymatically cleaved to the alcohol N methylscopine and dithienylglycolic acid, both not binding to muscarinic receptors.
In-vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (<20% of dose after intravenous administration) is metabolised by cytochrome P450 dependent oxidation and subsequent glutathione conjugation to a variety of Phase II-metabolites. This enzymatic pathway can be inhibited by the CYP450 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium bromide even in supra-therapeutic concentrations does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
Elimination: The effective half-life of tiotropium ranges between 27 to 45 h following inhalation by COPD patients. The effective half-life was 34 hours in patients with asthma.
Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After inhalation of the inhalation solution by COPD patients urinary excretion is 18.6% (0.93 μg) of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces.
In patients with asthma, 11.9% (0.595 μg) of the dose is excreted unchanged in the urine over 24 hours post dose at steady state.
The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once daily inhalation, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.
Linearity/nonlinearity: Tiotropium demonstrates linear pharmacokinetics in the therapeutic range independent of the formulation.
Elderly Patients: As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance from 347 mL/min in COPD patients <65 years to 275 mL/min in COPD patients ≥65 years. This did not result in a corresponding increase in AUC_0-6,ss or C_max,ss values.
Exposure to tiotropium was not found to differ with age in patients with asthma.
Renally Impaired Patients: Following once daily inhaled administration of tiotropium to steady-state in COPD patients with mild renal impairment (CL_cr 50-80 mL/min) resulted in slightly higher AUC_0-6,ss (between 1.8 to 30% higher) and similar C_max,ss compared to patients with normal renal function (CL_cr >80 mL/min). In COPD patients with moderate to severe renal impairment (CL_cr <50 mL/min) the intravenous administration of tiotropium bromide resulted in doubling of the total exposure (82% higher AUC_0-4h and 52% higher C_max) compared to COPD patients with normal renal function, which was confirmed by plasma concentrations after dry powder inhalation.
In asthma patients with mild renal impairment (CL_cr 50-80 mL/min) inhaled tiotropium did not result in relevant increases in exposure compared to patients with normal renal function.
Hepatically Impaired Patients: Liver insufficiency is not expected to have any relevant influence on tiotropium bromide pharmacokinetics. Tiotropium bromide is predominantly cleared by renal elimination (74% in young healthy volunteers) and simple non-enzymatic ester cleavage to pharmacologically inactive products.
Toxicology: The acute inhalation and oral toxicity in mice, rats, and dogs was low; therefore, toxic effects from acute human drug over-dosage are unlikely. The single dose safety pharmacology studies showed the expected effects of an anticholinergic drug including mydriasis, increased heart rate and prolonged gastro-intestinal transit time.
The side effects of the repeat-dose studies in rats, mice and dogs were related to anticholinergic properties of tiotropium bromide including mydriasis, increased heart rate, constipation, decreased body weight gain, reduced salivary and lacrimal gland secretion. Other relevant changes noted were: mild irritancy of the upper respiratory tract in rats evinced by rhinitis and epithelial changes of the nasal cavity and larynx, and prostatitis along with proteinaceous deposits and lithiasis in the bladder of male rats, increased lung weights in rats and decreased heart weights in dogs.
In the reproduction studies in rabbits and rats harmful effects with respect to pregnancy, embryo/foetal development, parturition or postnatal development could only be demonstrated at maternally toxic dose levels. In a general reproduction and fertility study in rats, there was no indication of any adverse effect on fertility or mating performance of either treated parents or their offspring at any dosage.
In a series of in vivo and in vitro mutagenicity assays, tiotropium bromide did not cause gene mutations in prokaryotes and in eucaryotes, chromosomal damage in vitro and in vivo conditions or primary DNA damage.

COPD: SPIRIVA RESPIMAT is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, the maintenance treatment of associated dyspnoea and for prevention of exacerbations.
Asthma: SPIRIVA RESPIMAT is indicated as add on maintenance treatment for the improvement of FEV₁ in adult patient with severe asthma who remain symptomatic on inhaled fluticasone.

The recommended dosage of SPIRIVA RESPIMAT is inhalation of the spray of two puffs once daily from the RESPIMAT inhaler at the same time of day (see Patient Counselling Information).
In the treatment of asthma, the full benefits will be apparent after several doses of SPIRIVA RESPIMAT.
Special populations: Elderly patients can use SPIRIVA RESPIMAT at the recommended dose.
Renally impaired patients can use SPIRIVA RESPIMAT at the recommended dose. However, as with all predominantly renally excreted drugs, SPIRIVA RESPIMAT use should be monitored closely in patients with moderate to severe renal impairment.
Hepatically impaired patients can use SPIRIVA RESPIMAT at the recommended dose.
Paediatric population: COPD does not normally occur in children. The safety and effectiveness of SPIRIVA RESPIMAT in paediatric patients have not been established.
The efficacy and safety of SPIRIVA RESPIMAT in paediatric patients with asthma has not yet been established.

High doses of SPIRIVA RESPIMAT may lead to anticholinergic signs and symptoms.
No relevant adverse events, beyond dry mouth/throat and dry nasal mucosa in a dose-dependent (10-40 µg daily) incidence, were observed following 14-day dosing of up to 40 µg tiotropium inhalation solution in healthy subjects with the exception of pronounced reduction in salivary flow from day 7 onwards. No significant undesirable effects have been observed in six long-term studies in COPD patients when a daily dose of tiotropium 10 µg inhalation solution was given over 4-48 weeks.

SPIRIVA RESPIMAT is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium or to any component of this product.

SPIRIVA RESPIMAT, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm or for the relief of acute symptoms. In the event of an acute attack, a rapid-acting beta-2-agonist should be used.
SPIRIVA RESPIMAT should not be used as a first-line treatment for asthma. Asthma patients must be advised to continue taking anti-inflammatory therapy, i.e. inhaled fluticasone, unchanged after the introduction of SPIRIVA RESPIMAT, even when their FEV₁ improve.
Immediate hypersensitivity reactions may occur after administration of SPIRIVA RESPIMAT inhalation solution.
As with other anticholinergic drugs, SPIRIVA RESPIMAT should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.
Inhaled medicines may cause inhalation-induced bronchospasm.
As with all predominantly renally excreted drugs, SPIRIVA use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of ≤50 ml/min).
Patients must be instructed in the correct administration of SPIRIVA RESPIMAT. Care must be taken not to allow the solution or mist to enter into the eyes. Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop specialist advice should be sought immediately.
Miotic eye drops are not considered to be effective treatment.
SPIRIVA RESPIMAT should not be used more frequently than once daily.
SPIRIVA cartridges are to be used only with the RESPIMAT inhaler.
Excipients: This medicine contains 0.0011 mg benzalkonium chloride in each actuation.
Benzalkonium chloride may cause wheezing and breathing difficulties. Patients with asthma are at an increased risk for these adverse events.
Effects on Ability to Drive and Use Machines: 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.

Pregnancy: There is a limited amount of data from the use of tiotropium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (see Pharmacology: Toxicology under Actions).
As a precautionary measure, it is preferable to avoid the use of SPIRIVA RESPIMAT during pregnancy.
Lactation: Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, a small amount of tiotropium is excreted into breast milk.
Therefore, SPIRIVA RESPIMAT should not be used in pregnant or nursing women unless the expected benefit outweighs any possible risk to the unborn child or the infant.
Fertility: Clinical data on fertility are not available for tiotropium. A non-clinical study performed with tiotropium showed no indication of any adverse effect on fertility (see Pharmacology: Toxicology under Actions).

Many of the listed undesirable effects can be assigned to the anticholinergic properties of SPIRIVA RESPIMAT.
Adverse drug reactions were identified from data obtained in clinical trials and spontaneous reporting during post approval use of the drug.
The clinical trial database for COPD includes 3,282 SPIRIVA RESPIMAT patients from 7 placebo-controlled clinical trials with treatment periods ranging between four weeks and one year, contributing 2,440 person years of exposure.
The clinical trial database for asthma includes 1,256 tiotropium treated patients from 6 placebo controlled trials with treatment period ranging between twelve weeks and one year, contributing 705 person years of exposure to tiotropium.
Metabolism and nutrition disorders: dehydration.
Nervous system disorders: dizziness, insomnia.
Eye disorders: glaucoma, intraocular pressure increased, vision blurred.
Cardiac disorders: atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia.
Respiratory, thoracic and mediastinal disorders: cough, epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis.
Gastrointestinal disorders: dry mouth (usually mild), constipation, oropharyngaeal candidiasis, dysphagia, gastrooesophageal reflux disease, gingivitis, glossitis, stomatitis, intestinal obstruction incl. ileus paralytic.
Skin and subcutaneous tissue disorders, Immune system disorders: rash, pruritus, angioneurotic oedema, urticaria, skin infection and skin ulcer, dry skin, hypersensitivity (including immediate reactions).
Musculoskeletal and connective tissue disorders: joint swelling.
Renal and urinary disorders: urinary retention (usually in men with predisposing factors), dysuria, urinary tract infection.

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 and asthma, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, anthihistamines, mucolytics, leucotriene modifiers, cromones and anti-IgE treatment without clinical evidence of drug interactions.
Common concomitant medications (LABA, ICS and their combinations) used by patients with COPD were not found to alter the exposure to tiotropium.
The chronic co-administration of tiotropium bromide with other anticholinergic drugs has not been studied. Therefore, the chronic co-administration of other anticholinergic drugs with SPIRIVA RESPIMAT is not recommended.

Store below 30°C. Do not freeze.

You will need to use this inhaler only ONCE A DAY. Each time you use it take TWO PUFFS.
How to care for your SPIRIVA RESPIMAT: 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.
When to get a new SPIRIVA RESPIMAT: Your SPIRIVA RESPIMAT inhaler contains 60 puffs (30 doses) if used as indicated (two puffs/Once daily).
The dose indicator shows approximately how much medication is left.
When the dose indicator enters the red area of the scale you need to get a new prescription; there is approximately medication for 7 days left (14 puffs).
Once the dose indicator reaches the end of the red scale, your SPIRIVA RESPIMAT locks automatically - no more doses can be released. At this point, the clear base cannot be turned any further.
Three months after first use, the SPIRIVA RESPIMAT should be discarded even if it has not been used.
Prepare for first use: 1. Remove clear base: Keep the cap closed.
Press the safety catch while firmly pulling off the clear base with your other hand.
2. Insert cartridge: Insert the narrow end of the cartridge into the inhaler.
Place the inhaler on a firm surface and push down firmly until it snaps into place.
3. Replace clear base: Put the clear base back into place until it clicks.
4. Turn: Keep the cap closed.
Turn the clear base in the direction of the arrows on the label until it clicks (half a turn).
5. Open: Open the cap until it snaps fully open.
6. Press: Point the inhaler toward the ground.
Press the dose-release button.
Close the cap.
Repeat steps 4-6 until a cloud is visible.
After a cloud is visible, repeat steps 4-6 three more times.
Daily use: TURN: Keep the cap closed.
TURN the clear base in the direction of the arrows on the label until it clicks (half a turn).
OPEN: OPEN the cap until it snaps fully open.
PRESS: Breathe out slowly and fully.
Close your lips around the mouthpiece without covering the air vents.
While taking a slow, deep breath through your mouth, PRESS the dose-release button and continue to breathe in.
Hold your breath for 10 seconds or for as long as comfortable.
Repeat Turn, Open, Press for a total of 2 puffs.

Antiasthmatic & COPD Preparations

R03BB04 - tiotropium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.

G