SPIRIVA Tiotropium Bromide Monohydrate 18mcg Powder in Capsule for Inhalation 1's

High doses of Tiotropium bromide (Spiriva/Spiriva Respimat) may lead to anticholinergic signs and symptoms.
Spiriva: However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in healthy volunteers. Bilateral conjunctivitis in addition to dry mouth was seen in healthy volunteers following repeated once-daily inhalation of 141 mcg in healthy volunteers, which resolved while still under treatment. In a multiple-dose study in COPD patients with a maximum daily dose of 36 mcg tiotropium over 4 weeks, dry mouth was the only observed adverse event attributable to tiotropium. Acute intoxication by oral ingestion of tiotropium capsules is unlikely due to low oral bioavailability.
Spiriva Respimat: 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 10 μg tiotropium inhalation solution was given over 4 - 48 weeks.

 

Spiriva: No clinical data on exposed pregnancies are available. Preclinical studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
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 should not be used in pregnant or nursing women unless the expected benefit outweighs any possible risk to the unborn child or infant.
Spiriva Respimat: Pregnancy: There is a limited amount of data from the use of tiotropium in pregnant women. Pre-clinical studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (please refer to Pharmacology: Toxicology under Actions). As a precautionary measure, it is preferable to avoid the use of Tiotropium bromide (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, Tiotropium bromide (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 pre-clinical study performed with tiotropium showed no indication of any adverse effect on fertility (please refer to Pharmacology: Toxicology under Actions).

 

 

Instructions for Use: Spiriva: The HandiHaler device is especially designed for Spiriva. It must not be used to take any other medication. HandiHaler device can be used for up to 1 year to take the medication.
1. Open the dust cap by pulling it upwards, then open the mouthpiece.
2. Remove the Spiriva capsule from the blister (only immediate before use) and place it in the centre chamber. It does not matter which way the capsule is placed in the chamber.
3. Close the mouthpiece firmly until a click is heard, leaving the dust cap open.
4. Hold the HandiHaler device with the mouthpiece upwards and press the piercing button completely at once, and release. This makes holes in the capsule and allows the medication to be released when the patient breathes-in.
5. Breathe-out completely.
Note: Avoid breathing into the mouthpiece at any time.
6. Raise the HandiHaler device to the mouth and close lips tightly around the mouthpiece. Keep head in an upright position and breathe-in slowly and deeply but at a rate sufficient to hear the capsule vibrate. Breathe until lungs are full; then hold breath as long as comfortable and at the same time take the HandiHaler device out of the mouth. Resume normal breathing. Repeat step 5 and 6 once, this will empty the capsule completely.
Open the mouthpiece again. Tip out the used capsule and dispose. Close the mouthpiece and dust cap for storage of the HandiHaler device.
Clean the HandiHaler device once a month. Open the dust cap and mouthpiece. Then open the base by lifting the piercing button. Rinse the complete inhaler with warm water to remove any powder. Dry the HandiHaler device thoroughly by tipping excess water out on a paper towel and air-dry afterwards, leaving the dust cap, mouthpiece and base open.
It takes 24 hrs to air dry, so clean it right after using it and it will be ready for the next dose. Outside of the mouthpiece may be cleaned with a moist but not wet tissue if needed.
The capsules should not be exposed, neither packed nor in the inhaler, to extreme temperatures ie, they should not be exposed to sunlight or to heating.
Spiriva Respimat: Introduction: Children should use Tiotropium bromide (Spiriva Respimat) with an adult's assistance.
Use this inhaler only ONCE A DAY. Each time using it take TWO PUFFS.
If not been used for more than 7 days release one puff towards the ground.
If not been used for more than 21 days repeat steps 4 to 6 until a cloud is visible. Then repeat steps 4 to 6 three more times.
How to care for Tiotropium bromide (Spiriva Respimat) reusable 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 the Tiotropium bromide (Spiriva Respimat) reusable inhaler performance.
If necessary, wipe the outside of the reusable inhaler with a damp cloth.
When to replace the inhaler: When the patient has used an inhaler with 6 cartridges, get a new Tiotropium bromide (Spiriva Respimat) pack containing an inhaler.
Prepare for first use: 1. Remove clear base: Keep the cap closed.
Press the safety catch while pulling off the clear base with the other hand.
2. Insert cartridge: Insert the cartridge into the inhaler.
Place the inhaler on a firm surface and push down firmly until it clicks into place.
3. Track cartridge: Mark the check-box on inhaler's label to track the number of cartridges.
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.
The inhaler is now ready to use and will deliver 60 puffs (30 doses).
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 full open.
Press: Breathe out slowly and fully.
Close the lips around the mouthpiece without covering the air vents. Point the inhaler to the back of the throat.
While taking a slow, deep breath through the mouth, PRESS the dose-release button and continue to breathe in slowly for as long as comfortable.
Repeat Turn, Open, Press for a total of 2 puffs.
Close the cap until the inhaler is used again.
When to replace the Tiotropium bromide (Spiriva Respimat) cartridge: The dose indicator shows how many puffs remain in the cartridge.
Less than 10 puffs remaining. Obtain a new cartridge.
When the cartridge is used up. Turn the clear base to loosen it. The inhaler is now in a locked position. Pull off the cartridge from the inhaler. Insert a new cartridge (continue with step 2).

 

Store at temperatures not exceeding 25°C.
Do not freeze.
Spiriva Respimat: Recommended use: 6 cartridges per inhaler.
Use within three months after the cartridge is inserted into the reusable inhaler.

 

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergics. ATC code: R03B B04.
Pharmacology: Pharmacodynamics: Mode of Action: 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 (Spiriva Respimat only). The bronchodilation following inhalation of tiotropium is primarily a local effect (on the airways) not a systemic one.
Clinical Trials: Spiriva: Cardiac electrophysiology: In a dedicated QT study involving 53 healthy volunteers, Tiotropium bromide (Spiriva) 18 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not prolong QT intervals of the ECG.
The clinical development program included four 1-year and two 6-month randomized, double-blind studies in 2663 patients with COPD (1308 receiving Spiriva). The 1-year program consisted of 2 placebo-controlled and 2 ipratropium-controlled trials. The 6-month trials were both, salmeterol- and placebo-controlled. These studies included evaluation of lung function, dyspnea, exacerbation of COPD and patients assessments of their health-related quality of life.
In the aforementioned studies, Spiriva administered once daily, provided significant improvement in lung function [forced expiratory volume in 1 sec (FEV₁) and forced vital capacity (FVC)] within 30 min following the 1st dose and was maintained for 24 hrs at steady state. Pharmacodynamic steady-state was reached within 1 week with the majority of bronchodilation observed by the 3rd day. Spiriva significantly improved morning and evening peak expiratory flow rate (PEFR) as measured by patient's daily recordings. The improvement in lung function with Spiriva was demonstrated throughout the period of administration in the 6 long-term trials. These improvements were maintained with no evidence of tolerance.
A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hr dosing interval in comparison to placebo regardless of whether Spiriva was administered in the morning or in the evening.
The following health outcome effects were demonstrated in the long-term (6-month and 1-year) trials: Tiotropium significantly improved dyspnea (as evaluated using the Mahler Transitional Dyspnea Index). This improvement was maintained throughout the treatment period.
Spiriva significantly reduced the number of COPD exacerbations and delayed the time to 1st exacerbation in comparison to placebo.
Spiriva significantly improved health-related quality of life as demonstrated by the disease-specific St. George's Respiratory Questionnaire. This improvement was maintained throughout the treatment period.
Additionally, in the 1-year placebo-controlled trials, Spiriva significantly reduced the number of hospitalisations associated with COPD exacerbations and delayed the time to 1st hospitalisation.
Spiriva Respimat: 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.

Pharmacokinetics: Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is administered by dry powder inhalation or is available as inhalation solution administered by the Respimat inhaler. Generally (for Spiriva) with the inhaled dose or route of administration, the majority of the delivered dose is deposited in the gastrointestinal tract, and to a lesser extent in the intended or target organ, the lung. Approximately 40% of the inhaled dose (of Spiriva Respimat) is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the pharmacokinetic data described as follows were obtained with higher doses as recommended for therapy.
Absorption: Following inhalation of dry powder or solution by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable (for Spiriva) and urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation (for Spiriva Respimat). It is expected from the chemical structure of the compound (quaternary ammonium compound) that tiotropium bromide is poorly absorbed from the gastrointestinal tract. 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 min (for Spiriva) and 5-7 minutes (for Spiriva Respimat) after inhalation.
Spiriva Respimat: 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 lungs are not known, but the mode of administration suggests substantially higher concentrations in the lungs. Studies in rats have shown that tiotropium bromide does not penetrate the blood-brain barrier to any relevant extent.
Spiriva: At steady state, tiotropium bromide plasma levels in COPD patients at peak were 17-19 pg/mL when measured 5 min after dry powder inhalation of a 18-mcg dose, and decreased rapidly in a multi-compartmental manner. Steady-state trough plasma concentrations were 3-4 pg/mL for Spiriva.
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: Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an interindividual variability of 22%. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After inhalation of dry powder or the inhalation solution by COPD patients urinary excretion is 14% and 18.6% (0.93 μg), respectively, of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces.
The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once daily inhalation, pharmacokinetic steady state was reached after 2-3 weeks (for Spiriva) and by day 7 (for Spiriva Respimat) with no accumulation thereafter.
Spiriva: The terminal elimination t_½ of tiotropium is between 5 and 6 days following inhalation.
Spiriva Respimat: 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.
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.
Linearity/nonlinearity: Tiotropium demonstrates linear pharmacokinetics in the therapeutic range independent of the formulation.
Specific Populations: Elderly Patients: Spiriva: As expected for all predominantly renally excreted drugs, advanced age was associated with a decrease of tiotropium renal clearance (326 mL/min in COPD patients <58 years to 163 mL/min in COPD patients >70 years) which may be explained by decreased renal function. Tiotropium bromide excretion in urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients), however, plasma concentrations did not change significantly with advancing age within COPD patients if compared to inter- and intraindividual variability (43% increase in AUC_{0-4 hrs} after dry powder inhalation).
Spiriva Respimat: 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.
Paediatric Patients: Spiriva Respimat: The peak and total exposure to tiotropium was not found to differ between paediatric patients (aged 6 to 17 years) and adults with asthma. In patients 1 to 5 years old with asthma, the total exposure as measured by urinary excretion was 52 to 60% lower than that observed in patients 6 years and older with asthma; the total exposure data when adjusted for body surface area were found to be comparable in all age groups. Tiotropium bromide (Spiriva Respimat) was administered with a valved holding chamber with facemask in patients 1 to 5 years of age.
Renally Impaired Patients: Spiriva: In common with all other drugs that undergo predominantly renal excretion, renal impairment was associated with increased plasma drug concentrations and reduced renal drug clearance after both IV infusion and dry powder inhalations. Mild renal impairment (CrCl 50-80 mL/min) which is often seen in elderly patients increased tiotropium or tiotropium bromide plasma concentrations slightly (39% increase in AUC_{0-4 hrs} after IV infusion).
In COPD patients with moderate to severe renal impairment (CrCl <50 mL/min), the IV administration of tiotropium or tiotropium bromide resulted in doubling of the plasma concentrations (82% increase in AUC_{0-4 hrs}), which was confirmed by plasma concentrations after dry powder inhalation.
Spiriva Respimat: 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 (CLcr >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 pharmacokinetics. Tiotropium 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 evidenced 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 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.
Spiriva Respimat: In juvenile rats exposed from postnatal day 7 to sexual maturity, the same direct and indirect pharmacological changes were observed as in the repeat-dose toxicity studies as well as rhinitis. No systemic toxicity was noted and no toxicologically relevant effects on key developmental parameters, tracheal or key organ development were seen.