Active ingredients: Tiotropium bromide
Spiriva Respimat 2.5 micrograms, solution for inhalation
Why is Spiriva respimat used? What is it for?
Spiriva Respimat 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 Respimat should be taken every day and not just when breathing difficulties or other symptoms occur.
Spiriva Respimat is a long-acting bronchodilator that dilates the bronchi and facilitates breathing. Regular use of Spiriva Respimat can also help when you develop shortness of breath associated with the disease and minimize the effects of the disease on daily life. Daily use of Spiriva Respimat helps prevent the sudden short-term worsening of COPD symptoms, which can last for several days.
For the correct dosage of Spiriva Respimat, please refer to section 3 "How to take Spiriva Respimat" and the "Instructions for Use" provided on the other side of the package leaflet.
Contraindications When Spiriva respimat should not be used
Do not take Spiriva Respimat
- if you are allergic (hypersensitive) to tiotropium, its active substance, or to any of the other ingredients of the medicine (listed in section 6)
- if you are allergic (hypersensitive) to atropine or to substances related to it, eg ipratropium or oxitropium.
Precautions for use What you need to know before taking Spiriva respimat
Please read the following questions carefully. If you have a positive answer to any question, talk to your doctor before starting Spiriva Respimat.
- are you allergic (hypersensitive) to tiotropium, atropine or similar substances such as ipratropium or oxitropium?
- 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 blurred vision, eye pain and / or red eyes, 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?
Talk to your doctor before taking Spiriva Respimat.
When taking Spiriva Respimat take care that the product does not get into your eyes. If this happens, you may experience pain or discomfort in the eyes, blurred vision, halos around lights or colored images associated with redness of the eyes (i.e. closed-angle glaucoma). Eye symptoms may be accompanied by headache, nausea, or vomiting. Rinse your eyes with warm water, stop taking tiotropium bromide and contact your doctor immediately for further advice.
If your breathing gets worse immediately after using the inhaler or if you experience skin irritation, swelling or itching, stop using it and tell your doctor immediately.
Long-term dry mouth that has been observed with anticholinergic treatment may be associated with dental caries. Therefore pay adequate attention to oral hygiene.
Spiriva Respimat is indicated for the maintenance treatment of chronic obstructive pulmonary disease. It must not be used to treat sudden attacks of shortness of breath or wheezing.
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 Respimat more than once a day. Also contact your doctor if you feel your breathing has got worse.
If you have cystic fibrosis, tell your doctor as Spiriva Respimat may make your cystic fibrosis symptoms worse.
Children and adolescents
Spiriva Respimat is not recommended for children and adolescents under the age of 18.
Interactions Which drugs or foods can modify the effect of Spiriva respimat
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those obtained without a prescription.
In particular, tell your doctor or pharmacist if you are taking or have taken anticholinergic medicines, for example ipratropium or oxitropium.
No undesirable effects of interaction have been reported after taking Spiriva Respimat in combination with other medicines used to treat COPD such as inhaled medicines that relieve symptoms such as salbutamol, methylxanthines, and / or orally administered steroids. or inhaled like prednisolone.
Warnings It is important to know that:
Pregnancy and breastfeeding
You should not use this medicine if you are pregnant, think you may be or are breastfeeding, unless specifically prescribed by your doctor.
Ask your doctor for advice before taking this medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. The onset of dizziness or blurred vision may affect the ability to drive or use machines.
Dose, Method and Time of Administration How to use Spiriva respimat: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, you should consult your doctor or pharmacist.
Spiriva Respimat is for inhalation use only.
The recommended dose for adults is:
Spiriva Respimat is effective for 24 hours therefore you will only need to take Spiriva Respimat ONCE A DAY, at the same time if possible. Each time he must take TWO DISPENSES.
As COPD is a chronic disease, take Spiriva Respimat every day and not just when you have trouble breathing. Do not take doses higher than recommended.
Spiriva Respimat is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.
Make sure you know how to use Spiriva Respimat properly. Instructions for using Spiriva Respimat are provided on the other side of this leaflet.
If you forget to take Spiriva Respimat
If you forget to take your daily dose (TWO DISPENSES ONCE A DAY), don't worry. Take it as soon as you remember, but do not take a double dose to make up for the forgotten. Take the next dose as usual.
If you stop taking Spiriva Respimat
Before stopping treatment with Spiriva Respimat, talk to your doctor or pharmacist. If you stop taking Spiriva Respimat the signs and symptoms of COPD may get worse.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Spiriva respimat
If you take more than two puffs of Spiriva Respimat in a day, contact your doctor immediately. You may be at increased risk of developing side effects such as dry mouth, constipation, difficulty urinating, increased heart rate or blurred vision.
Side Effects What are the side effects of Spiriva respimat
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 experienced by patients taking this medicine, are listed by frequency divided into common, uncommon, rare or not known.
Immediate allergic reactions such as rash, hives, swelling of the mouth and face or sudden difficulty in breathing (angioneurotic edema) or other hypersensitivity reactions (such as sudden drop in blood pressure or dizziness) which occur individually or may occur with Spiriva Respimat as part of a severe allergic reaction (anaphylactic reaction). If any of these occur, contact your doctor immediately.
Also, as with all other inhaled medicines, some patients may experience unexpected chest tightness, coughing, wheezing or shortness of breath immediately after inhalation (bronchospasm).
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 on the website of the Italian Medicines Agency: http://www.agenziafarmaco.gov.it/it/responsabili. information on the 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 on the label of the inhaler.
The expiry date refers to the last day of that month.
The Spiriva Respimat inhaler must be discarded no later than 3 months after first use (see "Instructions for Use" overleaf).
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.
Deadline "> Other information
What Spiriva Respimat contains
The active ingredient is tiotropium. The delivered dose is 2.5 micrograms of tiotropium per actuation (2 puffs constitute the drug strength) and is equivalent to 3.124 micrograms of tiotropium bromide monohydrate. The delivered dose is the dose available to the patient after passing through the mouthpiece.
The other ingredients are: benzalkonium chloride, sodium edetate, purified water and 3.6% hydrochloric acid as a pH adjuster.
What Spiriva Respimat looks like and contents of the pack
Spiriva Respimat 2.5 micrograms consists of a cartridge containing the solution for inhalation and a Respimat inhaler. The cartridge must be inserted into the inhaler before first use.
Single pack: 1 Respimat inhaler and 1 cartridge providing 60 puffs (30 doses of medicine)
Double pack: 2 single packs, each containing 1 Respimat inhaler and 1 cartridge providing 60 puffs (30 doses of medicine)
Triple pack: 3 single packs, each containing 1 Respimat inhaler and 1 cartridge providing 60 puffs (30 doses of medicine)
Pack of 8: 8 single packs, each containing 1 Respimat inhaler and 1 cartridge providing 60 puffs (30 doses of medicine)
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 RESPIMAT 2,5 MCG, SOLUTION FOR INHALATION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
The delivered dose is 2.5 mcg of tiotropium per actuation (2 puffs constitute the dose of the drug) and is equivalent to 3.124 mcg of tiotropium bromide monohydrate.
The delivered dose is the dose that is available to the patient after passing through the mouthpiece.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Solution for inhalation.
Clear and colorless inhalation solution.
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 intended for inhalation use only. The cartridge can only be inserted and used with the Respimat inhaler (see section 4.2).
Two puffs via the Respimat inhaler constitute one dose of the medicine.
The recommended dose for adults is 5 micrograms of tiotropium, administered as two puffs via the Respimat inhaler once a day, at the same time.
The recommended dose should not be exceeded.
Special populations
Elderly patients can use tiotropium bromide at the recommended posology.
Patients with renal insufficiency can use tiotropium bromide at the recommended posology. For patients with moderate to severe renal impairment (creatinine clearance ≤ 50 ml / min) see sections 4.4 and 5.2.
Patients with hepatic insufficiency can use tiotropium bromide at the recommended posology (see section 5.2).
Pediatric population
COPD
Spiriva Respimat is not used significantly in children and adolescents under the age of 18.
Cystic fibrosis
The efficacy and safety of Spiriva Respimat have not been established (see sections 4.4 and 5.1).
Method of administration
To ensure proper administration of the medicine, a doctor or other healthcare professional should show the patient how to use the inhaler.
Patient Instructions for Use and Handling
Spiriva Respimat inhaler and Spiriva Respimat cartridge
1) Inserting the cartridge
The following steps from 1 to 6 are required before first use:
1 Keeping the green cap closed, press the safety catch while pulling out the transparent base.
2 Take the cartridge out of the box. Insert the narrow end of the cartridge into the inhaler and push until you hear a click. The cartridge must be pushed firmly on a solid surface to make sure it is fully inserted.
The cartridge will not be close to the inhaler, the lower "silver" end of the cartridge will protrude.
Do not remove the cartridge once it has been inserted into the inhaler.
3 Reinsert the transparent base.
Do not remove the transparent base anymore.
2) Preparing the Spiriva Respimat inhaler for first use
4 Hold the Spiriva Respimat inhaler straight, with the green cap closed. Rotate the base in the direction of the black arrows on the label until you hear a click (half turn).
5 Snap the green cap and open it completely.
6 Point the Spiriva Respimat inhaler towards the ground.
Press the dose release button. Close the green cap.
Repeat steps 4, 5 and 6 until a cloud is visible.
Then repeat steps 4, 5 and 6 three more times to make sure the inhaler is ready for use.
Spiriva Respimat is now ready for use.
These steps will not affect the number of doses available. After its preparation, the Spiriva Respimat inhaler will be able to deliver 60 puffs (30 doses of medicine)
Daily use of the Spiriva Respimat inhaler
This inhaler will only need to be used ONCE A DAY.
Take TWO DISPENSES each time.
I Keep the Spiriva Respimat inhaler straight, with the green cap closed, to avoid accidental release of the dose. Rotate the base in the direction of the black arrows on the label until you hear a click (half turn).
II Snap off the green cap and open it completely. Breathe out slowly and completely, then close your lips around the end of the mouthpiece, without covering the ventilation holes. Direct the Spiriva Respimat inhaler towards the back of the throat.
Breathing in slowly and deeply from your mouth, press the dose release button and continue to breathe in slowly for as long as possible. Hold your breath for 10 seconds or as long as possible.
III Repeat steps I and II so that the full dose is taken.
The use of this inhaler is only necessary ONCE A DAY.
Close the green cap until the next use of the inhaler.
If the Spiriva Respimat inhaler is not used for more than 7 days, release one puff towards the ground. If Spiriva Respimat inhaler is not 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.
When to get a new pack of Spiriva Respimat
The Spiriva Respimat inhaler contains 60 puffs (30 doses of medicine). The dose indicator shows approximately how much medicine is left. When the indicator reaches the red area of the scale, there is medicine left for approximately 7 days (14 puffs). It's time to talk to your doctor.
When the dose indicator has reached the end of the red scale (ie all 30 doses have been used), the Spiriva Respimat inhaler is empty and locks automatically, no further doses can be released. At this point, the base can no longer be rotated over.
At the latest three months after first use Spiriva Respimat inhaler should be discarded even if not all of the medicine has been taken.
Maintenance of Spiriva Respimat inhaler
Clean the mouthpiece including the metal part inside it only with a damp cloth or paper towel, at least once a week.
Any slight discoloration of the mouthpiece does not affect the efficiency of the Spiriva Respimat inhaler.
If necessary, clean the outside of the Spiriva Respimat inhaler with a damp cloth.
04.3 Contraindications -
Spiriva Respimat is contraindicated in patients with hypersensitivity to tiotropium bromide, atropine or its derivatives, for example ipratropium or oxitropium or to any of the excipients (see section 6.1).
04.4 Special warnings and appropriate precautions for use -
Tiotropium bromide, being 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 following administration of tiotropium bromide solution for inhalation.
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.
Medicines administered by inhalation can cause inhalation-induced bronchospasm.
Tiotropium should be used with caution in patients with recent myocardial infarction for less than 6 months; in patients who have experienced any unstable or life-threatening arrhythmia or cardiac arrhythmia requiring intervention or modification of drug therapy in the previous year; in patients hospitalized for heart failure (NYHA Class III or IV) in the previous year. Such patients were excluded from clinical trials and these conditions may be affected by the anticholinergic mechanism of action.
Since 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 sprayed solution 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 associated 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.
Long-term dry mouth, which has been reported with anticholinergic treatment, may be associated with dental caries.
Tiotropium bromide should not be used more than once a day (see section 4.9).
Spiriva Respimat is not recommended in cystic fibrosis. When used in patients with cystic fibrosis, Spiriva Respimat may increase the signs and symptoms of the disease (eg serious adverse events, pulmonary exacerbations, respiratory tract infections).
04.5 Interactions with other medicinal products and other forms of interaction -
Although no formal drug interaction studies have been performed, tiotropium bromide has been used concomitantly with other medicinal products commonly used in the treatment of COPD, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, with no clinical evidence of interactions.
The use of LABA or ICS was not found to alter exposure to tiotropium.
Chronic co-administration of tiotropium bromide and other anticholinergic containing medicinal products has not been studied and is therefore not recommended.
04.6 Pregnancy and breastfeeding -
Pregnancy
For tiotropium bromide no clinical data on exposure in pregnancy are available. Studies in animals have shown reproductive toxicity associated with maternal toxicity (see section 5.3).
The potential risk to humans is unknown. Therefore, Spiriva Respimat 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 Respimat 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 Respimat should be made taking into account the benefit of breastfeeding for the child and therapy with Spiriva. Respimat 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 or blurred vision 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 tiotropium bromide.
Summary table of adverse reactions
The frequency assigned to the undesirable effects listed below is based on the crude rates of incidence of adverse drug reactions (i.e. events attributed to tiotropium bromide) observed in the tiotropium group, obtained by pooling data from 7 placebo-controlled clinical trials (3,282 patients ) which involved treatment periods ranging from four weeks to one year.
The frequency was defined on the basis of the following convention:
Very common (≥1 / 10); common (≥1 / 100,
Description of selected adverse reactions
In controlled COPD clinical trials, commonly observed undesirable effects were anticholinergic in nature, such as dry mouth which occurred in approximately 2.9% of patients.
Across the 7 COPD clinical trials, dry mouth led to treatment discontinuation in 3 of the 3,282 treated patients (0.1%).
Serious side effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction, including paralytic ileus and urinary retention.
Other special populations
An increase in anticholinergic effects may occur with increasing age.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
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. In addition to dry mouth / throat and nasal mucosa, no relevant adverse events were observed after 14 days of treatment with an inhaled solution of tiotropium up to 40 mcg in healthy volunteers, except for a pronounced reduction in saliva flow from the seventh day onwards.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: other drugs for obstructive respiratory tract syndromes, for inhalation, anticholinergics.
ATC code: R03B B04.
Mechanism of action
Tiotropium bromide is a specific long-acting muscarinic receptor antagonist. It has a similar affinity for muscarinic receptor subtypes M1 to M5. In the airways, tiotropium bromide binds competitively and reversibly to the M3 receptors of the bronchial smooth muscle, antagonizing the cholinergic (bronchoconstrictor) effects of acetylcholine, inducing relaxation of the bronchial smooth muscle. The effect is dose-dependent and lasts longer. 24 hours. Being an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before the onset of systemic anticholinergic effects.
Pharmacodynamic effects
The dissociation of tiotropium especially from M3 receptors is very slow showing a significantly longer dissociation half-life than that of ipratropium. controlled) for the M3 receptor subtype versus the M2 subtype. The high efficacy, slow dissociation from the receptor and topical inhalation selectivity are clinically reflected in significant and long-lasting bronchodilation in COPD patients.
Clinical efficacy and safety in COPD
The Phase III clinical development program included two 1-year studies, two 12-week studies and two 4-week, randomized, double-blind studies in 2,901 COPD patients (1,308 treated with 5 mcg tiotropium bromide). The one-year program consisted of two placebo-controlled studies. The two 12-week studies were controlled against both an active control medicine (ipratropium) and placebo. All six studies included lung function assessment. In addition, the two 1-year studies included assessments of dyspnoea, health-related quality of life and exacerbations.
Placebo-controlled studies
Lung function
Tiotropium solution for inhalation, given once daily, produced a significant improvement in lung function (forced expiratory volume in one second and forced vital capacity) within 30 minutes of the first dose compared to placebo (mean improvement in FEV1 at 30 minutes: 0.113 liters; 95% CI: 0.102 to 0.125 liters, m
Improvement in lung function was maintained at steady state for 24 hours compared to placebo (mean improvement in FEV1: 0.122 liters; 95% CI: 0.106 to 0.138 liters, p
Pharmacodynamic steady state was achieved within one week.
Spiriva Respimat significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patients' daily records compared to placebo (mean improvement in PEFR: mean morning improvement 22 l / min; 95% CI: 18 to 55 l / min, p
The bronchodilator effects of Spiriva Respimat were maintained over the 1 year dosing period without the onset of tolerance problems.
Dyspnoea, Health-related quality of life, COPD exacerbations in long-term 1-year studies
Dyspnea
Spiriva Respimat significantly improved dyspnoea (assessed using the transient dyspnoea index) compared to placebo (mean improvement 1.05 units; 95% CI: 0.73 to 1.38 units, p
Health-related quality of life
The improvement in the mean total score of the patient's assessment of their quality of life (measured using the St. George respiratory questionnaire) between Spiriva Respimat and placebo at the end of the two 1-year clinical trials was 3, 5 units (95% CI: 2.1 to 4.9, p
COPD flare-ups
In three one-year, randomized, double-blind, placebo-controlled clinical trials, treatment with Spiriva Respimat significantly reduced the risk of COPD exacerbations compared to placebo. COPD exacerbations were defined as "a combination of at least two respiratory events / symptoms lasting three days or more that required a change in treatment (prescription of systemic antibiotics and / or corticosteroids and / or a significant change in prescribed respiratory medication ) ". Treatment with Spiriva Respimat resulted in a reduced risk of hospitalization for COPD exacerbation (significant in the large appropriately powered exacerbation study).
The pooled analysis of two Phase III studies and the separate analysis of an additional exacerbation study are shown in Table 1. All respiratory medicinal products except anticholinergics and long-acting beta-agonists were permitted as concomitant therapy. , ie, short-acting beta-agonists, inhaled corticosteroids and xanthines. Long-acting beta-agonists were additionally permitted in the exacerbation study.
Table 1: Statistical Analysis of COPD Exacerbations and COPD Exacerbations with Hospitalization in Patients with Moderate to Very Severe COPD.
a Time to first event: days of treatment within which 25% of patients experienced at least one COPD exacerbation / COPD exacerbation with hospitalization. In study A 25% of patients treated with placebo had an exacerbation by day 112, while with Spiriva Respimat 25% had an exacerbation by day 173 (p = 0.09); in study B 25% of patients placebo-treated patients had an exacerbation by day 74, while with Spiriva Respimat 25% of patients had an exacerbation by day 149 (p
b Hazard ratios were estimated using the Cox proportional hazard model.The percentage of risk reduction is 100 (1 - hazard ratio).
c Poisson regression. The risk reduction is 100 (1 - rate ratio).
d Aggregation was specified when the studies were designed. Exacerbation endpoints were significantly improved in the individual analyzes of the two one-year studies.
Long-term controlled study against tiotropium
A long-term, large-scale, randomized, double-blind, active-treatment controlled study with an observation period of up to 3 years was conducted to compare the efficacy and safety of Spiriva Respimat and Spiriva HandiHaler (5,711 patients treated with Spiriva Respimat; 5,694 patients treated with Spiriva HandiHaler). The primary endpoints were time to first COPD exacerbation, time to death from all causes and, in a sub-study (906 patients), trough FEV1 (pre -dose).
Time to first COPD exacerbation was numerically similar during the study with Spiriva Respimat and Spiriva HandiHaler (hazard ratio (Spiriva HandiHaler / Spiriva Respimat) 0.98 with 95% CI 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 lasted for 120 weeks and was similar to that of Spiriva HandiHaler. The mean difference in trough FEV1 of Spiriva Respimat compared to that of Spiriva HandiHaler was -0.010 l (95% CI -0.038 to 0.018 L).
In the post-marketing TIOSPIR study comparing Spiriva Respimat and Spiriva HandiHaler, all cause mortality (including vital status follow up) was similar with a hazard ratio (Spiriva Respimat / Spiriva HandiHaler) = 0.96, with 95% CI 0.84 - 1.09). The exposure to the respective treatments was 13,135 and 13,050 patient-years.
In placebo-controlled studies with follow-up of vital status until the end of the planned treatment period, Spiriva Respimat showed a numerical increase in all-cause mortality compared to placebo (rate ratio (95% confidence interval) of 1 , 33), with 2,574 patient-years exposure to Spiriva Respimat treatment; excess mortality was observed in patients with known rhythm disturbances. Spiriva HandiHaler showed a 13% reduction in the risk of death (hazard ratio including vital status at follow up (tiotropium / placebo) = 0.87; 95 % CI, 0.76 to 0.99). Exposure to treatment with Spiriva HandiHaler was 10,927 patient-years. No excess risk of mortality was observed in the subgroup of patients with known rhythm disturbances in the placebo-controlled study with Spiriva HandiHaler, as well as in the TIOSPIR study comparing Spiriva Respimat versus Spiriva HandiHaler.
Pediatric population
COPD
The European Medicines Agency has waived the obligation to submit the results of studies with Spiriva Respimat in all subsets of the pediatric population in COPD (see section 4.2 for information on pediatric use).
Clinical efficacy and safety in cystic fibrosis
The clinical development program in cystic fibrosis included 3 multicenter studies conducted in 959 patients aged at least 5 months. Patients less than 5 years of age used a spacer (AeroChamber Plus) with face mask and were included for safety assessment only. The two pivotal studies (a Phase II dose finding study and a Phase III confirmatory study) compared the effects of Spiriva Respimat (tiotropium 5 mcg: 469 patients) on lung function (FEV1 expressed as a percentage of predicted AUC0- 4h and trough FEV1) versus placebo (315 patients) in 12-week randomized double-blind periods; the Phase III study also included a "long-term extension up to 12 months, open label. In these studies, all respiratory medications, except anticholinergics, such as long-acting beta-agonists, mucolytics were permitted as concomitant treatment. and antibiotics.
Effects on lung function are shown in Table 2. No significant improvement in symptoms and health status was observed (exacerbations as assessed by the Respiratory and Systemic Symptoms Questionnaire and quality of life as assessed by the Cystic Fibrosis Questionnaire).
Table 2: Adjusted mean difference from placebo for absolute changes from baseline after 12 weeks
a Co-primary endpoints
All adverse drug reactions observed in cystic fibrosis studies are undesirable effects of tiotropium (see section 4.8). The most commonly observed adverse events considered related during the 12-week double-blind period were cough (4.1%) and dry mouth (2.8%).
The number and percentage of patients reporting adverse events of particular concern in cystic fibrosis regardless of correlation are shown in Table 3. With tiotropium, the signs and symptoms considered manifestations of cystic fibrosis increased numerically, although not statistically significantly, mainly in patients aged ≤11 years.
Table 3: Percentage of patients with adverse events of particular interest in cystic fibrosis by age group over 12 weeks of treatment regardless of correlation (pooled Phase II and Phase III data)
"Distal intestinal obstruction syndrome" and "Increased" sputum "are MedDRA preferred terms." Respiratory tract infections "is the highest level MedDRA term in the group." Abdominal pain "," Constipation "and" Exacerbations "are collected of MedDRA preferred terms.
Thirty-four (10.9%) patients randomized to placebo and 56 (12.0%) patients randomized to Spiriva Respimat experienced a serious adverse event.
The European Medicines Agency has waived the obligation to submit the results of studies with Spiriva Respimat in the subgroup of the pediatric population less than 1 year of age.
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 available as an inhalation solution to be administered via the Respimat inhaler. Approximately 40% of the inhaled dose is deposited in the lungs, target organ, the rest in the gastrointestinal tract. Some of the pharmacokinetic data described below were 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 by healthy young volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. Food is not expected to affect the absorption of this quaternary ammonium compound.
Maximum plasma concentrations of tiotropium bromide were observed 5-7 minutes after inhalation.
At steady state, maximum plasma tiotropium levels of 10.5 pg / mL were reached in COPD patients and rapidly decreased in a multi-compartmental fashion. Steady state trough plasma concentrations were 1.60 pg / mL.
Systemic exposure to tiotropium following inhalation of tiotropium via the Respimat device was similar to that of inhaled tiotropium via the Handihaler device.
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 considerably higher concentrations in the lung. Studies in rats have shown that tiotropium does not cross the blood-brain barrier to any relevant 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 by cytochrome P450 (CYP) resulting in oxidation and subsequent conjugation with glutathione in a variety of Phase II metabolites.
In vitro studies in liver microsomes revealed that the enzymatic pathway can be inhibited by CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestoden. Thus CYP 2D6 and 3A4 are involved in the metabolic pathway which is responsible for eliminating 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 effective half-life of tiotropium is between 27 and 45 hours after inhalation in healthy volunteers and in COPD patients. Total clearance was 880 ml / min after intravenous administration in young healthy volunteers. When administered intravenously, tiotropium bromide is mainly excreted unchanged in the urine (74%).
After inhalation of the solution by COPD patients, at steady state, 18.6% (0.93 mcg) 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.
After inhalation of the solution by healthy volunteers, 20.1-29.4% 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.
Renal clearance of tiotropium exceeds creatinine clearance, indicating secretion in the urine.
After chronic inhalation once daily by COPD patients, steady-state pharmacokinetics were achieved by day 7 with no accumulation thereafter.
Linearity / non-linearity: Tiotropium demonstrates linear pharmacokinetics in the therapeutic range regardless of formulation.
c) Characteristics in patients
Elderly patients: As expected for all primarily renally excreted medicinal products, advancing age was associated with a decrease in renal clearance of tiotropium (from 347 ml / min in COPD patients aged
Patients with renal insufficiency: After once daily inhaled administration of tiotropium at steady state in COPD patients, mild renal insufficiency (ClCR 50-80 ml / min) resulted in a slightly higher AUC0-6, ss (between 1.8 and 30% greater) and similar values of Cmax, ss compared to patients with normal renal function (ClCR> 80 ml / min).
In COPD patients with moderate to severe renal impairment (ClCR
Patients with hepatic insufficiency: Hepatic insufficiency is assumed to have no relevant influence on the pharmacokinetics of tiotropium. Tiotropium is mainly excreted via the kidney (74% in healthy young volunteers) and through simple non-enzymatic dissociation of the ester into pharmacologically inactive products.
Japanese patients with COPD: In the cross-sectional comparator study, the mean peak plasma concentrations of tiotropium 10 minutes after dosing at steady state were 20% to 70% higher in Japanese COPD patients than in Caucasian patients following tiotropium inhalation, but not c "was an indication of higher mortality or cardiac risk in Japanese than Caucasian patients. Insufficient pharmacokinetic data are available for other ethnicities or races.
Pediatric patients:
Pediatric patients were not included in the COPD program (see section 4.2). Pediatric patients were studied as part of the cystic fibrosis clinical program that also covers adults.
After inhalation of 5 μg of tiotropium, the plasma level of tiotropium in patients with cystic fibrosis and aged ≥5 years was 10.1 pg / ml 5 minutes after steady-state dosing and then rapidly decreased. The fraction of the dose available in patients with cystic fibrosis and body weight age.
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, reproductive toxicity, can be explained by the anticholinergic properties of tiotropium bromide. Typical effects have been observed in animals: reduced food consumption and inhibition of weight gain, dry mouth and nose, reduced lacrimation and salivation, mydriasis and increased heart rate. Other relevant effects noted in repeated dose toxicity studies were: mild irritation of the respiratory tract in rats and mice evidenced by rhinitis and alterations of the epithelium of the nasal cavity and larynx, prostatitis accompanied by protein deposits and lithiasis in the rat bladder.
In juvenile rats exposed from day 7 of life to sexual maturity, the same direct and indirect pharmacological changes observed in repeat dose toxicity studies as well as rhinitis were observed. No systemic toxicity was found, no toxicologically relevant effects on key developmental parameters, trachea or key organ development were observed.
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) changes and reproductive toxicity were observed after local or systemic exposure to doses more than five 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 -
Benzalkonium chloride
Sodium edetate
Purified water
3.6% hydrochloric acid (as a pH adjuster)
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
During use: 3 months.
06.4 Special precautions for storage -
Do not freeze.
06.5 Nature of the immediate packaging and contents of the package -
Type and material of the container in contact with the medicinal product:
The solution is contained in a polyethylene / polypropylene cartridge with a polypropylene capsule with integrated sealing silicone ring. The cartridge is inserted inside an aluminum cylinder.
Packages and devices available.
Single pack: 1 Respimat inhaler and 1 cartridge providing 60 puffs (30 doses of medicine).
Double pack: 2 single packs, each containing 1 Respimat inhaler and 1 cartridge providing 60 puffs (30 doses of medicine).
Triple pack: 3 single packs, each containing 1 Respimat inhaler and 1 cartridge providing 60 puffs (30 doses of medicine).
Pack of 8: 8 single packs, each containing 1 Respimat inhaler and 1 cartridge providing 60 puffs (30 doses of medicine).
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
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 -
038880011 "2.5 mcg, solution for inhalation" 1 Respimat inhaler + 1 PE / PP cartridge of 60 puffs
038880023 "2.5 mcg, solution for inhalation" 2 Respimat inhalers + 2 PE / PP cartridges of 60 puffs
038880035 "2.5 mcg, solution for inhalation" 3 Respimat inhalers + 3 PE / PP cartridges of 60 puffs
038880047 "2.5 mcg, solution for inhalation" 8 Respimat inhalers + 8 PE / PP cartridges of 60 puffs
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
28 December 2010/24 July 2012
10.0 DATE OF REVISION OF THE TEXT -
March 4, 2015
