Active ingredients: Tiotropium
Spiriva 18 micrograms, inhalation powder, hard capsule
Indications Why is Spiriva used? What is it for?
Spiriva 18 micrograms helps people with chronic obstructive pulmonary disease (COPD) to breathe easier. COPD is a chronic lung disease that causes shortness of breath and cough. The term COPD is associated with chronic conditions of bronchitis and emphysema. Since COPD is a chronic disease, Spiriva 18 micrograms should be taken every day and not just when breathing difficulties or other COPD symptoms occur.
Spiriva 18 micrograms is a long-acting bronchodilator that helps dilate the airways and facilitate the entry and exit of air from the lungs. Regular use of Spiriva 18 micrograms can also help when you develop shortness of breath related to the disease and will help you minimize the effects of the disease on your everyday life. It also allows you to be active longer. Daily use of Spiriva 18 micrograms helps prevent the sudden short-term worsening of COPD symptoms, which can last for several days.
The effect of this medicine lasts for 24 hours, so it must be taken once a day. For the correct dosage of Spiriva 18 micrograms, see section 3. "How to take Spiriva 18 micrograms" and the instructions for use provided on the " other side of the leaflet
Contraindications When Spiriva should not be used
Please read the following questions carefully. If the answer to any question is positive, talk to your doctor before starting Spiriva 18 micrograms.
- are you allergic to tiotropium, atropine or similar substances such as ipratropium or oxitropium or to lactose or milk proteins?
- are you taking any other medicines that contain ipratropium or oxitropium?
- are you pregnant, do you think you are pregnant or are you breastfeeding?
- do you suffer from narrow-angle glaucoma, prostate problems or difficulty urinating?
- do you suffer from kidney problems?
- Have you suffered from myocardial infarction in the past 6 months or any form of unstable or life-threatening irregular heartbeat or severe heart failure in the past year?
Do not take Spiriva 18 micrograms
Do not take Spiriva 18 micrograms if you are allergic (hypersensitive) to tiotropium, the active substance, or to lactose monohydrate which contains milk proteins.
Also do not take Spiriva 18 micrograms if you are allergic (hypersensitive) to atropine or substances related to it, eg ipratropium or oxitropium.
Precautions for use What you need to know before taking Spiriva
- Tell your doctor if you have narrow-angle glaucoma, prostate problems or difficult urination.
- If you suffer from kidney problems, consult your doctor.
- Spiriva 18 micrograms is indicated for the maintenance therapy of chronic obstructive pulmonary disease, it should not be used to treat a sudden attack of shortness of breath or shortness of breath.
- Immediate allergic reactions such as rash, swelling, itching, wheezing or shortness of breath may occur after administration of Spiriva 18 micrograms. If this happens, consult your doctor immediately.
- Medicines taken by inhalation such as Spiriva 18 micrograms may cause chest tightness, cough, shortness of breath or shortness of breath immediately after administration. If this happens, consult your doctor immediately.
- Carefully avoid inhalation dust coming into contact with your eyes as this can cause precipitation or worsening of narrow-angle glaucoma, which is an eye disease. Pain or discomfort in the eyes, blurred vision, halos around lights or colored images in association with red eyes may be signs of an acute attack of narrow-angle glaucoma. Ocular symptoms may be accompanied by headache, nausea or vomiting. Stop taking tiotropium bromide and consult your doctor immediately, preferably an eye specialist, if any signs and symptoms of narrow angle glaucoma appear.
- Dry mouth, which has been observed during treatment with anticholinergics, may in the long term be associated with dental caries. Therefore a thorough dental hygiene is recommended.
- If you have suffered from myocardial infarction in the past 6 months or any form of unstable or life-threatening irregular heartbeat or severe heart failure in the past year, please tell your doctor. This information is important in determining whether Spiriva is the right medicine for you.
- Do not take Spiriva 18 micrograms more frequently than once a day.
Children and adolescents
Spiriva 18 micrograms is not recommended for children and adolescents under 18 years of age.
Interactions Which drugs or foods can change the effect of Spiriva
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those obtained without a prescription.
Tell your doctor or pharmacist if you are taking or have recently taken similar medicines for your lung disease, such as ipratropium or oxitropium.
No specific side effects have been reported after taking Spiriva 18 micrograms in combination with other medicines used to treat COPD such as inhaled medicines that relieve symptoms such as salbutamol, methylxanthines such as theophylline and / or steroids given to orally or by inhalation such as prednisolone
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or think you are pregnant or breastfeeding, consult your doctor.
Do not use this medicine unless specifically recommended by your doctor.
Driving and using machines
The onset of dizziness, blurred vision or headache may affect the ability to drive or use machines.
Spiriva 18 micrograms contains lactose monohydrate.
Each capsule provides up to 5.5 mg of lactose monohydrate, when Spiriva 18 micrograms is taken according to the recommended dosage of one capsule once daily.
Dosage and method of use How to use Spiriva: Dosage
Always take Spiriva 18 micrograms exactly as your doctor has told you. If you are not sure you should consult your doctor or pharmacist.
The recommended dose is inhalation of the contents of one capsule (18 micrograms of tiotropium) once a day. Do not take more than the recommended dose.
Spiriva 18 micrograms is not recommended for children and adolescents under 18 years of age.
The capsule should be taken at the same time each day. This is important as Spiriva 18 micrograms is effective for 24 hours.
The capsules are for inhalation only and not for oral administration.
Do not swallow the capsules.
The HandiHaler device, inside which the Spiriva capsule must be placed, pierces the capsule and allows the inhalation of the powder.
Make sure you have a HandiHaler and know how to use it properly. Instructions for using the HandiHaler are provided on the other side of this leaflet.
Make sure you don't blow into the HandiHaler.
If you are unsure about how to use HandiHaler, ask your doctor, nurse or pharmacist who will show you how it works.
The HandiHaler should be cleaned once a month. Instructions for cleaning the HandiHaler are provided on the other side of this leaflet.
When taking Spiriva 18 micrograms, take care that the powder does not get into your eyes. If this happens you may experience blurred vision, pain and / or redness of the eyes, in this case you should immediately rinse your eyes with lukewarm water. Then contact your doctor immediately for further advice.
If you find that your breathing has got worse, tell your doctor as soon as possible.
Overdose What to do if you have taken too much Spiriva
If you take more Spiriva 18 micrograms than you should
If you inhale the contents of more than one capsule of Spiriva 18 micrograms in a day, you should contact your doctor immediately. You may be at an increased risk of experiencing side effects such as dry mouth, constipation, difficulty urinating, increased heart rate or blurred vision.
If you forget to take Spiriva 18 micrograms
If you forget to take a dose, take it as soon as you remember, but do not take a double dose at the same time or on the same day. Then take your next dose as usual.
If you stop taking Spiriva 18 micrograms
Before stopping treatment with Spiriva 18 micrograms, you should talk to your doctor or pharmacist.
If you stop taking Spiriva 18 micrograms the signs and symptoms of COPD may get worse.
If you have any further questions on the use of this medicine, ask your doctor.
Side Effects What are the side effects of Spiriva
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The evaluation of undesirable effects is based on the following frequencies:
Common: may affect up to 1 in 10 people
Uncommon: may affect up to 1 in 100 people
Rare: may affect up to 1 in 1,000 people
Not known: frequency cannot be estimated from the available data
The side effects described below have been reported by people who have taken this medicine and are listed by frequency divided into common, uncommon, rare or not known.
Common:
- dry mouth: usually mild
Uncommon:
- dizziness
- headache
- changes in taste
- blurred vision
- irregular heartbeat (atrial fibrillation)
- inflammation of the throat (pharyngitis)
- hoarse voice (dysphonia)
- cough
- heartburn (gastroesophageal reflux disease)
- constipation
- fungal infections of the mouth and throat (oropharyngeal candidiasis)
- rash
- difficulty urinating (urinary retention)
- pain when urinating (dysuria)
Rare:
- difficulty sleeping (insomnia)
- visual halos around lights or colored images associated with red eyes (glaucoma)
- increase in measured eye pressure
- irregular heartbeat (supraventricular tachycardia)
- rapid heartbeat (tachycardia)
- perception of heartbeat (palpitations)
- chest tightness, associated with coughing, wheezing or shortness of breath immediately after inhalation (bronchospasm)
- nose bleeding (epistaxis)
- inflammation of the larynx (laryngitis)
- inflammation of the sinuses (sinusitis)
- blockage of the bowel or absence of bowel movements (intestinal obstruction including paralytic ileus) D
- inflammation of the gums (gingivitis)
- inflammation of the tongue (glossitis)
- difficulty swallowing (dysphagia)
- inflammation of the mouth (stomatitis)
- feeling sick (nausea)
- hypersensitivity, including immediate reactions
- severe allergic reactions causing swelling of the face or throat (angioedema)
- urticaria
- itch
- urinary tract infections
Not known:
- loss of body fluids (dehydration)
- dental caries
- severe allergic reaction (anaphylactic reaction)
- skin infections or ulcerations
- dryness of the skin
- swelling of the joints.
Serious side effects may occur following administration of Spiriva 18 micrograms which include allergic reactions causing swelling of the face or throat (angioedema) or other hypersensitivity reactions (such as sudden drop in blood pressure or dizziness) which occur individually or as part of the a severe allergic reaction (anaphylactic reaction). Also, as with other inhaled medicines, some patients may experience unexpected chest tightness, coughing, wheezing or shortness of breath immediately after inhalation (bronchospasm). If you get any of these effects, see your doctor immediately.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister strip. The expiry date refers to the last day of that month.
Having taken the first capsule from the blister strip, continue to extract the next ones for nine days, one capsule per day, from the same blister strip.
Do not store above 25 ° C.
Do not freeze.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Spiriva 18 micrograms contains
Each capsule contains 18 micrograms of the active ingredient tiotropium (as bromide monohydrate).
During the inhalation 10 micrograms of tiotropium are released from the mouthpiece of the HandiHaler.
The excipient is lactose monohydrate.
What Spiriva 18 micrograms looks like and contents of the pack
Spiriva 18 micrograms, inhalation powder, hard capsule is a light green hard capsule with the product code TI 01 and the company logo printed.
The product is available in the following packages:
Pack containing 30 capsules
Pack containing 60 capsules
Pack containing 10 capsules and 1 HandiHaler device
Pack containing 30 capsules and 1 HandiHaler device
Hospital pack: containing 5 cartons of 30 capsules and HandiHaler device
Hospital pack: containing 5 packs of 60 capsules
Also available is a pack containing 1 HandiHaler device.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SPIRIVA 18 mcg, POWDER FOR INHALATION, RIGID CAPSULE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 22.5 mcg of tiotropium bromide monohydrate equivalent to 18 mcg of tiotropium.
The delivered dose (dose that is released from the mouthpiece of the HandiHaler device) is 10 mcg of tiotropium.
Excipients: Lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Inhalation powder, hard capsule.
Light green hard capsules, with the product code TI 01 and the company logo printed on the capsule.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Tiotropium is indicated for maintenance bronchodilator therapy in the relief of symptoms in patients with chronic obstructive pulmonary disease (COPD).
04.2 Posology and method of administration
Dosage
The medicinal product is for inhalation use only.
The recommended dosage of tiotropium bromide is the inhalation of the contents of one capsule once a day, at the same time, with the HandiHaler device.
The recommended dose should not be exceeded.
Tiotropium bromide capsules are for inhalation only and not for oral administration.
Tiotropium bromide capsules should not be swallowed.
Tiotropium bromide should only be inhaled with the HandiHaler device.
Special populations
Elderly patients can use tiotropium bromide at the recommended dose.
Patients with renal insufficiency can use tiotropium bromide at the recommended dose. For patients with moderate to severe renal impairment (creatinine clearance ≤50 ml / min) see section 4.4 and section 5.2.
Patients with hepatic insufficiency can use tiotropium bromide at the recommended dose (see section 5.2).
Pediatric population
COPD
There is no significant use in the pediatric population (under 18 years) in the indication described in section 4.1.
Cystic fibrosis
The safety and efficacy of Spiriva in children and adolescents has not been established. There are no data available.
Method of administration
To ensure correct administration of the medicinal product, the patient must be instructed on the use of the inhaler by the doctor or other healthcare professional.
Instructions for handling and use
Remember to carefully follow the instructions given by your doctor for using Spiriva. The HandiHaler device has been specially developed for Spiriva. You should not use it to take any other medicines. You can use the HandiHaler device for up to one year to take the medicine.
Description of HandiHaler
1 Dustproof closing cap
2 Mouthpiece
3 Base
4 Punch button
5 Central chamber
1. To unlock the dust cap, press the puncture button completely and then release it.
2. Fully open the dust cap by lifting it upwards.
Then open the mouthpiece by pushing it upwards.
3. Take a capsule of Spiriva out of the blister (just before use) and insert it into the central chamber as shown. It does not matter which way the capsule is oriented in the chamber.
4. Close the mouthpiece tightly until a click is heard, leaving the dust cap open.
5. Hold the HandiHaler device with the mouthpiece facing up and press the puncture button fully once and release.
This action creates holes in the capsule which allows the medicine to be released during inspiration.
6. Breathe out completely.
Important: Always avoid breathing into the mouthpiece.
7. Bring the HandiHaler device to your mouth and close your lips firmly around the mouthpiece. Hold your head upright and inhale slowly and deeply but at a speed sufficient to hear or feel the capsule vibrate.
Inhale until the lungs are full; then hold your breath as long as possible and at the same time remove the HandiHaler device from your mouth.
Resume breathing normally.
Repeat steps 6 and 7 once in order to completely empty the capsule.
8. Open the mouthpiece again. Turn the used capsule upside down and throw it away. Close the mouthpiece and dust cap to store the HandiHaler device.
Cleaning the HandiHaler device
Clean the HandiHaler device once a month. Open the dust cap and mouthpiece. Then open the base by lifting the punch button. Rinse the entire inhaler with warm water to remove dust. Dry the HandiHaler device thoroughly by spilling excess water onto a paper towel and leaving it in the air, keeping the dust cap, mouthpiece and base open. it takes 24 hours to air dry, the device must be cleaned immediately after use to be ready for the next inhalation. If necessary, the outside of the mouthpiece can be cleaned with a damp but not wet cloth.
Using the blister strip
A. Divide the blister strip in half by pulling along the perforated line
B. Lift the sheet on the back face using the tab until a capsule is completely visible (only immediately before use).
If a second capsule is inadvertently exposed to air, it must be discarded.
C. Take out the capsule.
Spiriva capsules contain only a small amount of powder, so the capsule is only partially filled.
04.3 Contraindications
Tiotropium bromide inhalation powder is contraindicated in patients with a hypersensitivity to tiotropium bromide, atropine or its derivatives, for example ipratropium or oxitropium or to the excipient lactose monohydrate which contains milk proteins.
04.4 Special warnings and appropriate precautions for use
Tiotropium bromide, a maintenance bronchodilator, to be taken once daily, should not be used in the initial treatment of acute episodes of bronchospasm, as an emergency therapy.
Immediate hypersensitivity reactions may occur after administration of tiotropium bromide inhalation powder.
In line with its anticholinergic activity, tiotropium bromide should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction (see section 4.8).
Medicines administered by inhalation can cause inhalation-induced bronchospasm.
As the plasma concentration of the medicinal product increases with decreasing renal function, in patients with moderate to severe renal impairment (creatinine clearance ≤50 ml / min), tiotropium bromide should only be used if the expected benefits outweigh the potential risks. There are no long-term data in patients with severe renal impairment (see section 5.2).
Patients should be advised to avoid the drug powder coming into contact with the 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 colored images in association with red eyes from conjunctival congestion and corneal edema. Should any combination of these ocular symptoms develop, patients should discontinue use of tiotropium bromide and consult a specialist immediately.
The dry mouth that has been observed with anticholinergic treatment in the long term may be associated with dental caries.
Tiotropium bromide should not be used more than once a day (see section 4.9).
Spiriva capsules contain 5.5 mg of lactose monohydrate.
04.5 Interactions with other medicinal products and other forms of interaction
Although no formal drug interaction studies have been performed, tiotropium bromide inhalation powder has been used concomitantly with other medicinal products without clinical evidence of interactions. These include sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, commonly used in the treatment of COPD.
Co-administration of tiotropium bromide and other anticholinergic containing medicinal products has not been studied and is therefore not recommended.
04.6 Pregnancy and lactation
Pregnancy
No documented clinical data on exposure in pregnancy are available for tiotropium bromide. Studies in animals have shown reproductive toxicity associated with maternal toxicity (see section 5.3). The potential risk for humans is unknown. Therefore Spiriva should only be used in pregnancy when clearly indicated.
Feeding time
It is not known whether tiotropium bromide is excreted in human milk. Although studies in rodents have shown that only a small amount of tiotropium bromide is excreted in breast milk, the use of Spiriva is not recommended during lactation. Tiotropium bromide is a long-acting substance. The decision to continue or discontinue breastfeeding rather than to continue or discontinue therapy with Spiriva should be made taking into account the benefit of breastfeeding for the child and therapy with Spiriva for the mother.
Fertility
No clinical data on fertility are available for tiotropium. A non-clinical study conducted with tiotropium did not reveal any adverse effects on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed. The occurrence of dizziness, blurred vision or headache may affect the ability to drive and use machines.
04.8 Undesirable effects
Summary of the safety profile
Many of the listed side effects can be attributed to the anticholinergic properties of Spiriva.
Summary table of adverse reactions
The frequency assigned to the undesirable effects listed below is based on the crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (9,647 patients), obtained by pooling data from 28 placebo-controlled clinical trials. which involved treatment periods ranging from four weeks to four years.
Frequency is defined on the basis of the following convention:
Very common (≥1 / 10); common (≥1 / 100,
Description of selected adverse reactions
In controlled clinical trials, the commonly observed side effects were anticholinergic side effects, such as dry mouth which occurred in approximately 4% of patients.
In 28 clinical studies, dry mouth led to treatment discontinuation by 18 of 9,647 patients treated with tiotropium (0.2%).
Serious side effects consistent with anticholinergic effects include glaucoma, constipation and intestinal obstruction including paralytic ileus as well as urinary retention.
Other special populations
An increased incidence of anticholinergic effects may occur with increasing age.
04.9 Overdose
High doses of tiotropium bromide can induce anticholinergic signs and symptoms.
However, no anticholinergic systemic adverse effects were observed in healthy volunteers following inhalation of a single dose of up to 340 mcg tiotropium bromide. Furthermore, no relevant adverse effects other than dry mouth were observed following administration. of tiotropium bromide up to 170 micrograms for 7 days In a multiple-dose study conducted in COPD patients treated with a maximum daily dose of 43 micrograms of tiotropium bromide for 4 weeks, no significant undesirable effects were observed.
Tiotropium bromide is characterized by low oral bioavailability, therefore inadvertent ingestion of oral capsules is unlikely to cause acute intoxication.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other drugs for obstructive respiratory tract syndromes for aerosols, anticholinergics, ATC code: R03B B04
Mechanism of action
Tiotropium bromide is a long-acting muscarinic receptor antagonist, in clinical practice often referred to as an anticholinergic. By binding to the muscarinic receptors of the bronchial smooth muscle, tiotropium bromide inhibits the cholinergic (bronchoconstrictor) effects of acetylcholine, released by parasympathetic nerve endings. It has a similar affinity for muscarinic subtypes M1 to M5. In the airways, tiotropium bromide competitively and reversibly antagonizes M3 receptors by inducing relaxation of bronchial smooth muscle. The effect was dose-dependent and lasted for more than 24 hours. The long duration is probably due to its very slow dissociation from M3 receptors, showing a significantly longer dissociation half-life than that of ipratropium. Being an N-quaternary anticholinergic tiotropium bromide is (broncho-) selective when administered by inhalation (topical ), demonstrating an acceptable therapeutic range before the onset of systemic anticholinergic effects.
Pharmacodynamic effects
Bronchodilation is primarily a local (airway) effect, not a systemic effect. Dissociation from M2 receptors is faster than from M3 receptors and this resulted in (kinetically controlled) selectivity for the M3 receptor subtype compared to the M2 subtype in functional in vitro studies. The high efficacy and slow dissociation from the receptor are clinically reflected in significant and long-lasting bronchodilation in COPD patients.
Cardiac electrophysiology
Electrophysiology: In a specific QT study conducted in 53 healthy volunteers, Spiriva at a dose of 18 mcg and 54 mcg (ie three times the therapeutic dose) administered for 12 days did not significantly prolong the QT intervals of the ECG.
Clinical efficacy
The clinical development program included 4 one-year and 2 six-month, randomized, double-blind studies in 2,663 patients (1,308 treated with tiotropium bromide). The one-year program consisted of 2 placebo-controlled studies and 2 studies against an active control medicine (ipratropium). The two six-month studies were both controlled for salmeterol and placebo. These studies included assessment of lung function and dyspnoea, exacerbations and health-related quality of life.
In the studies mentioned above, tiotropium bromide, given once daily, produced a significant improvement in lung function (forced expiratory volume in one second, FEV1, and forced vital capacity, FVC) within 30 minutes of the first dose and was maintained for 24 hours.Steady-state pharmacodynamics were achieved within one week with the greatest bronchodilation effect observed by the third day. Tiotropium bromide significantly improved the morning and evening peak expiratory flow (PEF) measured from the patients' daily records. The bronchodilator effects of tiotropium bromide were maintained throughout the year of administration without the onset of tolerance.
A randomized, placebo-controlled clinical trial in 105 COPD patients showed that bronchodilation was maintained over the 24-hour treatment interval compared to placebo, regardless of whether the medicine was administered in the morning or in the evening.
The following effect has been shown in long-term studies (6 months and one year):
tiotropium bromide significantly improved dyspnoea (assessed using the transient dyspnoea index). This improvement was maintained for the duration of treatment.
The effect of improved dyspnoea on exercise tolerance was evaluated in two randomized, double-blind, placebo-controlled studies involving 433 patients with moderate to severe COPD. In these studies, treatment for six weeks with Spiriva produced a significant improvement in symptom-limited exercise endurance time measured on the cycle ergometer to 75% of maximal work capacity, or 19.7%, (study A: 640 seconds with Spiriva vs. 535 seconds with placebo , compared with a pre-treatment baseline of 492 seconds) and 28.3% (study B: 741 seconds with Spiriva vs. 577 seconds with placebo, compared with a pre-treatment baseline of 537 seconds).
In a randomized, double-blind, placebo-controlled study in 1,829 patients with moderate to very severe COPD, tiotropium bromide statistically significantly reduced the percentage of patients experiencing COPD exacerbations (from 32, 2% to 27.8%) and statistically significantly reduced the number of exacerbations by 19% (from 1.05 to 0.85 events per patient per year of exposure). In addition, 7.0% of patients treated with tiotropium bromide and 9.5% of patients in the placebo group were hospitalized for COPD exacerbations (p = 0.056). The number of hospital admissions caused by COPD was reduced by 30% (0.25 to 0.18 events per patient per year of exposure).
In a 9-month, randomized, double-blind, placebo-controlled study of 492 patients, Spiriva improved health-related quality of life as determined by the St. Georgès Respiratory Questionnaire (SGRQ) total score. . The percentage of patients treated with Spiriva who achieved a significant improvement in the SGRQ total score (i.e.> 4 units) was 10.9% higher than that treated with placebo (59.1% in the Spiriva group versus 48 , 2% in the placebo group (p = 0.029)). The mean difference between the two groups was 4.9 units (p = 0.001; confidence interval: 1.69 - 6.68). of the SGRQ score were 8.19 units for “symptoms,” 3.91 units for “activity,” and 3.61 units for “impact on daily life.” The improvements in all of these individual subdomains were statistically significant.
In a 4-year, randomized, double-blind, placebo-controlled clinical study involving 5,993 patients (3,006 on placebo and 2,987 on Spiriva), the improvement in FEV1 due to administration of Spiriva, compared to placebo, remained constant for 4 years. A higher proportion of patients in the Spiriva group than in the placebo group (63.8% vs. 55.4%, p
Treatment with tiotropium reduced the risk of respiratory failure (as indicated by the adverse event record) by 19% (2.09 vs. 1.68 cases per 100 patients per year, relative risk (tiotropium / placebo) = 0.81 , 95% CI = 0.65, 0.999).
A one-year, randomized, double-blind, double-dummy, parallel group clinical trial compared the effect of treatment with Spiriva 18 mcg once daily with the effect of treatment with salmeterol 50 mcg. administered twice daily with a pressurized dose inhaler (HFA pMDI), on the incidence of moderate and severe exacerbations in 7,376 patients with COPD and a history of exacerbations in the previous year.
Table 1: Summary of the exacerbation endpoints
† Time [days] refers to the first quartile of patients. Time to event analysis was performed using Cox proportional hazards regression model with center (aggregate) and treatment as covariates, ratio refers to hazard ratio.
§ The time to event analysis was performed using the Cox proportional hazards regression model with center (aggregate) and treatment as covariates, the ratio refers to the hazard ratio. The time [days] for the first quartile of patients cannot be calculated, because the percentage of patients with severe exacerbation was too low.
* The number of patients with event was assessed using the Cochran-Mantel-Haenszel test stratified by pooled center; the ratio refers to the risk ratio.
Compared to salmeterol, Spiriva increased the time to first exacerbation (187 days versus 145 days), with a 17% risk reduction (hazard ratio, 0.83; 95% confidence interval [CI], from 0.77 at 0.90; p
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Spiriva in all subsets of the pediatric population in COPD and cystic fibrosis (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
a) General introduction
Tiotropium bromide is a non-chiral quaternary ammonium compound and is moderately soluble in water. Tiotropium bromide is administered as a powder for inhalation. Generally by inhalation, most of the delivered dose is deposited in the gastrointestinal tract, and to a lesser extent in the target organ which is the lung. Many of the pharmacokinetic data described below have been obtained with doses higher than those recommended for therapy. .
b) General characteristics of the active ingredient after administration of the medicinal product
Absorption: After inhalation of the dry powder by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. From the chemical structure of the compound (quaternary ammonium compound) and from in vitro studies it is expected that tiotropium bromide is poorly absorbed from the gastrointestinal tract (10-15%). Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. Maximum plasma concentrations of tiotropium bromide were observed five minutes after inhalation. Food does not appear to affect the absorption of this quaternary ammonium compound.
Distribution: The medicinal product is 72% bound to plasma proteins and exhibits a volume of distribution of 32 l / kg. At steady-state, peak plasma tiotropium bromide levels in COPD patients were 17-19 pg / mL when measured 5 minutes after inhalation of an 18 mg dry powder dose and rapidly decreased in a multi-compartmental fashion. The steady-state trough plasma concentration was 3-4 pg / ml. Local concentrations in the lung are unknown, but the mode of administration suggests considerably higher concentrations in the lung. Studies in rats have shown that tiotropium bromide does not cross the blood-brain barrier to any significant extent.
Biotransformation: The extent of biotransformation is low. This is evident from the urinary excretion of 74% of the unchanged drug after intravenous administration in young healthy volunteers. The tiotropium bromide ester is non-enzymatically cleaved into the alcohol (N-methylscopine) and the acid compound (dithienylglycolic acid) which are inactive on muscarinic receptors. In-vitro experiments with liver microsomes and human hepatocytes suggest that additional (intravenous) drug is metabolized with cytochrome P450 (CYP) dependent oxidation and subsequent conjugation with glutathione in a variety of Phase II metabolites.
In vitro studies in liver microsomes reveal that the enzymatic pathway can be inhibited by CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus the cytochrome CYP 2D6 and 3A4 are involved in the metabolic pathway which is responsible for the elimination of a smaller part of the dose.
Tiotropium bromide even in concentrations above therapeutic ones does not inhibit CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
Elimination: The terminal elimination half-life of tiotropium bromide is between 5 and 6 days after inhalation. Total clearance was 880 mL / min following an intravenous dose in young healthy volunteers with individual variability of 22%. Intravenously administered tiotropium bromide is mainly excreted unchanged in the urine (74%). After inhaled administration of the dry powder 14% of the dose is excreted via the urine and the remainder, being a drug mainly not absorbed from the intestine, is eliminated in the faeces. The renal clearance of tiotropium bromide exceeds the creatinine clearance. , indicating secretion in the urine. After chronic daily inhalation by COPD patients, pharmacokinetic steady-state was reached after 2-3 weeks with no subsequent accumulation.
Linearity / non-linearity: Tiotropium bromide demonstrates linear pharmacokinetics in the therapeutic range both after intravenous administration and after inhalation of the dry powder.
c) Characteristics in patients
Elderly patients: As expected for all primarily renally excreted medicinal products, older age was associated with a decrease in renal clearance of tiotropium bromide (from 326 ml / min in COPD patients aged 70 years) which could be explained by decreased renal function. The excretion of tiotropium bromide in urine after inhalation decreased from 14% (healthy young volunteers) to approximately 7% (patients with COPD); however, plasma concentrations did not significantly change with advancing age in COPD patients when compared to inter- and intraindividual variability (43% increase in AUC0-4h after inhalation of dry powder).
Patients with renal insufficiency: As with all medicinal products which are excreted primarily via the kidney, renal failure has been associated with increased plasma concentrations of the medicinal product and reduced renal clearance of the medicinal product, both after intravenous infusion and after inhalation. Renal failure mild (CLCR 50-80 ml / min) which is often present in elderly patients slightly increases plasma concentrations of tiotropium bromide (39% increase in AUC0-4h after intravenous infusion). In COPD patients with moderate to severe (CLCR
Patients with hepatic insufficiency: Hepatic insufficiency is assumed to have no relevant influence on the pharmacokinetics of tiotropium bromide. Tiotropium bromide is primarily excreted via the kidney (74% in young healthy volunteers) and through simple non-enzymatic dissociation of the ester into pharmacologically inactive products.
Pediatric patients: see section 4.2.
d) Relations between pharmacokinetics and pharmacodynamics
There is no direct correlation between pharmacokinetics and pharmacodynamics.
05.3 Preclinical safety data
Many effects observed in conventional studies of drug tolerance, repeated dose toxicity and reproductive toxicity can be explained by the anticholinergic properties of tiotropium bromide. Typical effects have been observed in animals: reduced food consumption and inhibited weight gain, dry mouth and nose, reduced lacrimation and salivation, mydriasis and increased heart rate. Other relevant effects noted in repeat dose toxicity studies were: mild irritation of the respiratory tract in rats and mice evidenced by rhinitis and changes in the epithelium of the nasal cavity and larynx, prostatitis accompanied by protein deposits and lithiasis in the bladder of the rat.
Adverse effects on pregnancy, embryonic / fetal development, parturition or postnatal development can only be demonstrated at maternally toxic dosages. Tiotropium bromide was not teratogenic in rats or rabbits. In a general reproduction and fertility study conducted in rats, there was no indication of any adverse effects on the fertility and mating ability of either the treated parents or their offspring at any dosage.
Respiratory (irritation) and urogenital (prostatitis) alterations and reproductive toxicity have been observed after local or systemic exposures more than 5 times higher than the therapeutic one. Studies on genotoxicity and carcinogenic potential did not reveal a particular risk for humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate (which contains milk proteins)
06.2 Incompatibility
Not relevant
06.3 Period of validity
2 years
After first opening the blister strip: 9 days
Discard the HandiHaler device 12 months after first use.
06.4 Special precautions for storage
Do not store above 25 ° C.
Do not freeze.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / PVC / Aluminum blister strip containing 10 capsules.
HandiHaler is a device for inhaling single doses of tiotropium, made of plastic (ABS) and stainless steel.
Packaging and device:
Pack containing 30 capsules (3 blister strips)
Pack containing 60 capsules (6 blister strips)
Pack containing HandiHaler device and 10 capsules (1 blister strip)
Pack containing HandiHaler device and 30 capsules (3 blister strips)
Hospital pack: containing 5 cartons of 30 capsules and HandiHaler device
Hospital pack: containing 5 packs of 60 capsules
The HandiHaler device is available in a cardboard box.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein - Germany
LEGAL REPRESENTATIVE IN ITALY
Boehringer Ingelheim Italia S.p.A.
Via Lorenzini, 8
20139 Milan
08.0 MARKETING AUTHORIZATION NUMBER
035668019 30 capsules in 18 mcg AL / PVC / AL blisters
035668021 60 capsules in 18 mcg AL / PVC / AL blisters
035668033 case with HandiHaler device
035668045 10 capsules in 18 mcg AL / PVC / AL blister with HandiHaler device
035668058 30 capsules in 18 mcg AL / PVC / AL blister with HandiHaler device
035668060 5 cartons of 30 capsules in 18 mcg AL / PVC / AL blister with HandiHaler device
035668072 5 cartons of 60 capsules in 18 mcg AL / PVC / AL blisters
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
13 May 2004/9 October 2006
10.0 DATE OF REVISION OF THE TEXT
April 2, 2014
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