Date of approval.
Tiotropium Ondatrol Inhalation Spray
Please read the instructions carefully and use under the guidance of your physician
[Drug Name].
Generic name: Tiotropium Ondatrol Inhalation Spray
Trade name: Spiolto® Respimat®
English Name: Tiotropium Bromide and Olodaterol Hydrochloride Inhalation Spray
Hanyu Pinyin: Saituoxiu’an Aodateluo Xirupenwuji
[Ingredients
This product is a compound preparation, the active ingredients are Tiotropium bromide and Aldactone hydrochloride.
Titropium bromide.
Chemical name: (1a,2b,4 b,5a,7b)3-oxo-9-azonotricyclo[3.3.1.02,4]nonane,7 -[(Hydroxy-bis-2-thienylacetyl)oxy]-9,9-dimethyl, bromide, monohydrate
Chemical structure formula.
Molecular Formula: C19H22NO4S2Br-H2O
Molecular weight: 490.4
Odaterol Hydrochloride.
Chemical name: 2H-1,4-benzoxazin-3H(4H)-one,6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-,monohydrochloride
Chemical structure formula.
Molecular Formula: C21H26N2O5-HCl
Molecular weight: 422.91
Excipients: benzalkonium chloride, disodium edetate, 1M hydrochloric acid, water for injection.
[Properties
This product is a colorless clarified liquid in a plastic vial covered with an aluminum shell, which is inserted into the inhaler and sprayed out in a mist when the inhaler is pressed.
[Indications][Indications][Indications family:Times New Roman”>
This product is indicated for the long-term maintenance treatment of patients with chronic obstructive pulmonary disease (COPD, or slow-onset lung, including chronic bronchitis and emphysema) to relieve symptoms.
[Specifications]
Each vial of 60 sprays contains 2.5µg of Tiotropium (equivalent to 3.124µg of Tiotropium Monohydrate) and 2.5µg of Odaterol (equivalent to 2.736µg of Odaterol Hydrochloride) per spray.
[dosage]
This product should only be used by inhalation. The vial can only be inserted into and used by inhalation through the Nembutal® inhaler.
Two snares of medication from the Nembutal® inhaler is one medicinal dose.
The recommended dose for adults is 5 μg of Tiotropium and 5 μg of Odatrol, 2 snaps per inhalation, once daily, at the same time each day through the Nembutal® inhaler (see [Instructions for Use]).
The recommended dose should not be exceeded.
Instructions for use
Please read the instructions for use carefully before starting to use this product.
Only use this product once a day. You need to spray 2 snaps per application.
Noble ® inhaler diagram
If the product has not been used for more than 7 days, 1 snap should be released towards the ground first.
If the product has not been used for more than 21 days, repeat steps 4 through 6 under “Prepare for initial use” until you see a spray of water. Then repeat steps 4 through 6 three more times.
Do not touch the needles in the clear base.
Maintenance of NIBEL®® Inhaler
Clean the inhaler, including the metal part inside the inhaler, with a damp cloth or wet paper towel only, at least once a week.
Some slight discoloration on the nozzle will not affect the performance of this inhaler.
If necessary, wipe the outer surface of the NIBEL® inhaler with a damp cloth.
When do you need a new Tiotropium Odatrol Inhalation Spray
This inhalation spray contains 60 snappers (30 medicinal doses) and should be used as directed (2 snappers once daily).
The medication dose indicator shows the approximate amount of medication remaining.
A new dose of Tiotropium Odatrol Inhalation Spray is needed when the dose indicator needle enters the red zone of the scale, when approximately 7 days of dose (14 snaps) remain.
Once the medication dose indicator pointer reaches the end of the red scale, the Nembutal® inhaler for this product automatically locks in place, indicating that no more dose can be released. At this point, the transparent base can no longer be rotated.
Three months after the initial use of this product, the medication should be discarded even if it has not been used up.
Preparation for initial use
Remove the transparent base
Leave the dust cap closed.
Press down on the safety catch while using your other hand to firmly pull off the clear base. Insert pill bottle
Insert the thin end of the vial into the inhaler.
Place the inhaler on a firm plane and press down firmly to get it well aligned.
Do not remove the vial once it has been inserted into the inhaler. Reinstall the transparent base
Reinstall the clear base back to its original position until it clicks.
Do not disassemble the clear base again. rotate
Keep the dust cap closed.
Rotate the clear base in the direction of the arrow on the inhaler label until it clicks (i.e., halfway through the rotation). Open
Open the dust cap fully. Press
Point the inhaler at the ground.
Cover the dust cap.
Repeat steps 4-6 until seeing a spray of water.
Repeat steps 4-6 three more times after you see the water spray.
Now you are ready to start using your Nemblix® inhaler. These steps will not affect the medicinal dose available for this product. After completing the above preparation steps, the product will be able to deliver 60 snaps (30 medicinal doses) to you.
Daily use
Rotation
Keep the dust cap closed.
Rotate the clear base in the direction of the arrow on the inhaler label until it clicks (i.e., halfway through the rotation). Open
Turn the dust cap fully open. Press
Exhale slowly and fully.
Hold the end of the inhaler with your lips, but do not block the vent. Point the inhaler toward the back of the throat.
Inhale slowly and deeply through your mouth while pressing the medication release button, then continue to inhale slowly and for as long as tolerated.
Hold your breath for 10 seconds or as long as you can tolerate.
Repeat the rotate, open, and press steps for a total of 2 snares of inhalation.
Close the dust cap until the Nemblix ® inhaler is used again. [Adverse Reactions]
a. Overview of security features
Most of the listed adverse reactions can be attributed to the anticholinergic properties of tiotropium, an ingredient in this combination, or to the b2-adrenergic properties of odaterol.
b. Adverse Reactions Overview
The incidence of adverse reactions listed below is based on the adverse drug reactions observed in the tiotropium 5µg/odaterol 5µg dose group (5646 patients) in eight parallel-group, active-controlled or placebo-controlled clinical trials conducted in patients with chronic obstructive pulmonary disease lasting from 4 weeks to 52 weeks of treatment (i.e., those related to tiotropium The approximate incidence of adverse drug reactions (i.e., events related to odaterol inhalation spray) observed in the 5646 patients in the tiotropium 5µg/odaterol dose group (5646 patients).
All adverse reactions reported in clinical trials of this combination are shown below by system organ classification.
All adverse reactions previously reported with the two single ingredients are also included here.
Frequency of occurrence is defined as follows.
very common (≥ 1/10); common (≥ 1/100 to < 1/10); occasional (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1,000); very rare (< 1/10,000); unclear ( cannot be estimated based on available data).
Infection and transmission.
Unspecified: nasopharyngitis
Metabolic and nutritional abnormalities.
Unspecified: dehydration
Neurological abnormalities.
Sometimes: dizziness, headache
Rarely: insomnia
Eye abnormalities.
Rare: blurred vision
Unclear: glaucoma, intraocular pressure Elevated
Cardiac abnormalities.
Sometimes: tachycardia
Rarely: atrial fibrillation, supraventricular tachycardia, palpitations
Vascular abnormalities.
Rare: Hypertension
Respiratory, thoracic and mediastinal abnormalities.
Sometimes: cough, vocal difficulties
Rarely: laryngitis, pharyngitis, epistaxis Bronchospasm
Unclear: sinusitis
Gastrointestinal abnormalities.
Sometimes: dry mouth
Rarely: constipation, oropharyngeal candidiasis disease, gingivitis, stomatitis, nausea
Unspecified: intestinal obstruction (including paralytic intestinal obstruction), dysphagia, gastroesophageal reflux disease, glossopharyngitis, dental caries
Dermal and subcutaneous tissue abnormalities, immune system abnormalities.
Rare: hypersensitivity reactions, vascular neuroedema, urticaria, rash, pruritus
Unspecified: rapid-onset hypersensitivity reactions Unspecified: tachyphylaxis, skin infections and skin ulcers, dry skin
Musculoskeletal and connective tissue abnormalities.
Rare: joint pain, back pain1, joint swelling
Kidney and urinary tract abnormalities.
Rare: urinary retention, urinary tract infections, and Difficulty in urination
1Reported for this combination and not reported for single-ingredient preparations Adverse reactions.
c. Specific Adverse Reaction Description
This combination has both anticholinergic and β2-adrenergic properties due to the presence of tiotropium and odaterol components.
Anticholinergic Adverse Reaction Profile.
In a 52-week long-term clinical trial with this combination, a common anticholinergic adverse reaction was dry mouth, with an incidence of approximately 1.3% in patients in the combination treatment group and 1.7% and 1% in patients in the tiotropium 5 μg and odalaterol 5 μg groups, respectively. Dry mouth led to discontinuation in 2/4968 (0.04%) of patients treated with this combination.
Serious adverse reactions associated with anticholinergic properties include glaucoma, constipation, intestinal obstruction (including paralytic intestinal obstruction), and urinary retention.
beta-adrenergic adverse reactions characterized by.
Odaterol, one of the ingredients of this compound, is a long-acting beta2-adrenergic receptor agonist drug. Therefore, other adverse reactions associated with the beta-adrenergic agonist class not listed above should be considered, such as arrhythmias, myocardial ischemia, angina pectoris, hypotension, tremor, headache, nervousness, nausea, muscle cramps, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis.
d. Other Special Populations
Anticholinergic effects may be enhanced with age.
[Taboo]
It is contraindicated in patients with hypersensitivity to tiotropium, orodaterol, or any of the excipients in this combination.
It is also contraindicated in patients with a history of hypersensitivity to atropine or its derivatives (e.g., ipratropium or oxytetracycline).
All long-acting beta2-adrenergic agonists (LABAs) are contraindicated in patients with asthma who are not on long-term controlled medications (see [Precautions]). This combination is not indicated for the treatment of asthma.
[Precautions]
General Warnings
This product should not be used more than once a day.
Asthma
This product should not be used for the treatment of asthma. The effectiveness and safety of this product for the treatment of asthma have not been studied.
Asthma-related deaths
Data from a large placebo-controlled study in patients with asthma suggest that long-acting beta2-adrenergic agonists (LABAs), such as odaterol (one of the active ingredients in this combination), may increase the risk of asthma-related death. There are no data to determine whether long-acting β2–adrenergic receptor agonists increase mortality in patients with chronic obstructive pulmonary disease.
Data from a 28-week, placebo-controlled US study comparing the safety of adding another long-acting β2-adrenergic agonist (salmeterol) or placebo to conventional asthma therapy showed an increase in asthma-related deaths in patients treated with salmeterol (13/13, 176 in patients treated with salmeterol compared with 3/13, 179 in patients treated with placebo; relative risk 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is thought to be a class effect of long-acting β2-adrenergic receptor agonists, including odaterol, one of the active ingredients of this combination. Studies sufficient to determine whether asthma-related mortality is elevated in patients treated with this combination formulation have not been performed. The safety and efficacy of this combination formulation in patients with asthma have not been established. This combination is not indicated for the treatment of asthma. (See [Contraindications])
Disease exacerbation and acute exacerbation
This combination should not be used to treat acute exacerbations (potentially life-threatening) of chronic obstructive pulmonary disease in patients. Studies have not been conducted with this combination in patients with acute exacerbation of slow-onset lung disease. In such cases, this combination is not indicated.
This compound should not be used to relieve acute symptoms, i.e., not as an emergency treatment drug for acute attacks of bronchospasm. Studies have not been conducted on the use of this combination for acute symptom relief, and additional doses should not be used to achieve acute symptom relief. Acute symptoms should be treated by inhaled short-acting beta2-agonists.
When initiating treatment with this combination, patients already receiving regular treatment with inhaled short-acting β2-agonists (eg, 4 times daily) should be instructed to discontinue regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing this combination, healthcare providers should also prescribe inhaled short-acting beta2-agonists and instruct patients on their use. Increased use of inhaled beta2-agonists is a sign of worsening disease and needs to be medically monitored as soon as possible.
Chronic obstructive pulmonary disease can deteriorate rapidly within hours or slowly over several days or more. If this combination does not continue to control the symptoms associated with bronchoconstriction, or if the patient’s inhaled short-acting β2-agonist is less effective, or if the patient needs to inhale more short-acting β2-agonists than usual, these may be signs of worsening disease. In such cases, the patient and the chronic obstructive pulmonary treatment regimen should be immediately reevaluated. Increasing the daily dose of this compound and exceeding the recommended dose in this situation is inappropriate.
overdose with this compound and with long-actingbeta2receptor agonists in combination
As with other inhaled medications containing beta2-adrenergic drugs, this combination should not be used more frequently than the recommended daily dose, at higher than recommended doses, or in combination with other drugs containing long-acting beta2-agonists, as these practices may lead to drug overdose. Clinically significant cardiovascular effects and deaths associated with overdose of inhaled sympathomimetic drugs have been previously reported.
Acute bronchospasm
This compound is not indicated for the treatment of acute attacks of bronchospasm, i.e. not to be used as an emergency treatment drug.
hypersensitivity reaction
Typical hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash, bronchospasm, severe tachyphylaxis, or pruritus, may occur after administration of this combination. If such reactions occur, treatment with this combination should be discontinued immediately and other treatment should be considered. Given the similar structural formula of tiotropium and atropine, patients with a history of hypersensitivity reactions to atropine and its derivatives should be closely monitored for similar hypersensitivity reactions when using this combination.
paradoxical bronchospasm
Like other inhaled medications, this combination may cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm occurs, discontinue this combination immediately and switch to other alternative treatments.
Narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction
Given the anticholinergic activity of tiotropium, this combination should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction (e.g., dysuria, painful urination). If any of these signs or symptoms occur, seek immediate medical attention.
Patients with liver injury and kidney injury
Thitropium, a drug contained in this product, is a drug that is primarily excreted by the kidneys and odaterol, a drug that is primarily metabolized by the liver.
Patients with liver injury
Patients with mild and moderate liver injury may use this product at the recommended dose.
There are no data on the use of odaterol in patients with severe liver injury.
Patients with kidney injury
Dose adjustment is not necessary for the use of this product in patients with renal impairment.
Because tiotropium is primarily excreted renally, patients with moderate to severe renal impairment (creatinine clearance<50mL/min) should be closely monitored for anticholinergic-related side effects when administering this combination (see [DOSAGE AND ADMINISTRATION]).
This product contains odaterol, and there is limited experience with odaterol in patients with severe kidney injury.
Ocular symptoms
Patients must be instructed in the proper use of this compound. Care must be taken to avoid getting the solution or spray into the eye. Ocular pain or discomfort, blurred vision, red eyes associated with conjunctival congestion, and visual halos or colored images associated with corneal edema may be signs of acute narrow-angle glaucoma. If any of these symptoms occur, patients should discontinue this combination immediately and seek the advice of their physician.
Pupil reduction eye drops are not an effective treatment.
Dental caries
Dry mouth was observed during treatment with anticholinergic drugs, and prolonged dry mouth may be associated with dental caries.
Systemic effects
This compound contains a long-acting beta2-adrenergic receptor agonist. Beta2-adrenergic agonists should be used with caution in patients with cardiovascular disease, especially in patients with coronary artery insufficiency, severe cardiac dysfunction, arrhythmias, hypertrophic obstructive cardiomyopathy, hypertension, and aneurysms; patients with convulsive disorders or hyperthyroidism, patients with known or suspected prolonged QT interval; and patients with abnormal reactions to sympathomimetic amines. patients with an abnormal response to sympathomimetic amines.
Cardiovascular effects
Patients with a history of myocardial infarction, unstable or life-threatening arrhythmias in the previous year, hospitalization for heart failure in the previous year, or a diagnosis of paroxysmal tachycardia (beats per minute>100) were excluded from clinical trials, and therefore the use of this combination in patients with such a history of Experience with this compound is limited. This combination should be used with caution in these patients.
As with other β2-adrenergic agonists, odaterol may produce effects with clinically significant cardiovascular effects in some patients, as evidenced by an increased pulse rate, elevated blood pressure, and/or increased symptoms. Once these effects occur, treatment may need to be discontinued. In addition, β-adrenergic agonists have been reported to induce electrocardiographic (ECG) changes such as T-wave depression, QTc interval prolongation, and ST-segment depression, but the clinical significance of these observations is unknown. Long-acting β2-adrenergic agonists should be used with caution in patients with vascular disease, particularly in patients with coronary artery supply deficiencies, arrhythmias, hypertrophic obstructive cardiomyopathy, and hypertension.
hypokalemia
β2-adrenergic agonists may cause significant hypokalemia in some patients, which may result in cardiovascular side effects. The decrease in blood potassium is usually transient and does not require potassium supplementation. In patients with severe chronic obstructive pulmonary disease, hypokalemia may be exacerbated by hypoxia as well as by combination therapy (see [Drug Interactions]), which may increase the patient’s susceptibility to cardiac arrhythmias.
Hyperglycemia
Inhalation of high doses of beta2-adrenergic receptor agonists may elevate blood glucose levels.
Comorbid Diseases
As with other sympathomimetic amines, odaterol should be used with caution in patients with convulsive disorders or hyperthyroidism, known or suspected prolongation of the QT interval, and in patients with abnormal responses to sympathomimetic amines. Several intravenous doses of the related β2-agonist salbutamol have been reported to exacerbate preexisting diabetes mellitus and ketoacidosis.
Anesthesia
Caution is required in the setting of elective surgery with halothane anesthetics due to increased susceptibility to cardiac adverse reactions associated with beta-agonist-like bronchodilators.
Impact on driving and manipulating mechanical ability
No studies have been conducted on the effects of this compound on driving and mechanical maneuverability.
However, patients should be advised that dizziness or blurred vision has been reported with this combination. Therefore, this combination should be used with caution when driving a vehicle or operating machinery. If patients experience these symptoms, they should avoid potentially risky tasks such as driving or operating machinery.
[For Pregnant and Lactating Women][For Pregnant and Lactating Women][For Pregnant and Lactating Women “font-family:Times New Roman”>
Pregnancy
As a precautionary measure, it is best to avoid the use of this compound during pregnancy.
with otherβ2-adrenergic receptor agonists, due to the relaxing effect on uterine smooth muscle, the ingredient Odaterol in this compound formulation may inhibit labor.
Thiotropium
There is very limited data on the use of tiotropium (tiotropium) in women during pregnancy. Animal studies have shown no direct or indirect harmful effects related to reproductive toxicity when given at clinically relevant doses (see [Toxicology Studies]).
Odaterol
For odaterol, there are no available clinical data on pregnancy exposure. Preclinical data for odaterol suggest that the typical effects of beta-adrenergic agonists are seen when given at high therapeutic doses (see [Toxicology Study]).
Lactation
Clinical data are not available on exposure to tiotropium and/or odaterol in lactating women.
In animal studies with tiotropium and odaterol, the drug components and/or their metabolites have been detected in the milk of lactating rats, but it is not known whether tiotropium and/or odaterol pass into human milk. The decision to discontinue breastfeeding or to forgo treatment with this combination should be made after considering the benefit to the nursing infant and the therapeutic benefit to the mother.
Fertility
Clinical data on the effect of tiotropium and odalterol or a combination of the two on fertility are not yet available.
[Pediatric use]
There is no relevant experience with the use of this compound in pediatric patients (under the age of 18 years). The safety and efficacy of this compounded formulation in pediatric patients have not been established.
[Geriatric use]
Geriatric patients may use this compound at the recommended dose.
[Drug Interactions]
While formal drug interaction studies have not been conducted, no clinical evidence of drug interactions has been found for this combination when used in combination with other commonly used drugs for the treatment of chronic obstructive pulmonary disease, including short-acting sympathomimetic bronchodilators and inhaled steroid hormones.
Anticholinergics
The long-term combination of tiotropium and other anticholinergic drugs has not been studied. Superimposed interactions may occur with the combined use of multiple anticholinergic drugs. Therefore, the long-term combination of this compound with other anticholinergic drugs is not recommended.
Adrenergic drugs
If additional adrenergic drugs are given by any route of administration, they may potentiate the sympathomimetic effects of odaterol and should be used with caution.
Xanthine derivatives, corticosteroids or diuretics
Tiotropium has been administered as a combination drug with short- and long-acting bronchodilators sympathomimetics (beta-agonists), methylxanthines, and oral and inhaled corticosteroids without increased adverse effects. Coadministration of xanthine derivatives, corticosteroids, or nonpotassium-preserving diuretics may potentiate the hyperkalemic effects of adrenergic agonists (see [Precautions]).
Non-potassium-preserving diuretics
β-agonists can acutely exacerbate ECG changes and/or hypokalemia caused by non-potassium-preserving diuretics (e.g., tab diuretics or thiazide diuretics), especially when the recommended dose of the β-agonist is exceeded. Although the clinical significance of these effects is not known, caution is recommended when this compound is co-administered with a non-potassium preserving diuretic.
β-receptor blockers
The combination of a beta-adrenergic receptor antagonist (beta-blocker) and odaterol (one of the components of this combination) may interfere with each other’s effects. beta-blockers not only impede the therapeutic effects of beta-agonists in patients with chronic obstructive pulmonary disease, but can also cause severe bronchospasm. Therefore, patients with chronic obstructive pulmonary disease usually cannot be treated with beta-blockers. However, in some cases, such as as as a prophylactic measure after myocardial infarction in patients with slow-onset lung, there may not yet be an acceptable alternative to beta-blockers. In such cases, cardioselective β-blockers may be considered, but should still be administered with caution.
monoamine oxidase inhibitors (MAO), tricyclic antidepressants, prolongedQTcinterval medications
Monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval may potentiate the effects of this combination on the cardiovascular system. Drugs known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.
Pharmacokinetic interactions between drugs
No effects related to systemic exposure to odaterol were observed in drug interaction studies in combination with fluconazole used as a model CYP2C9 inhibitor.
The combination with ketoconazole, a potent P-gp and CYP3A4 inhibitor, resulted in an approximate 70% increase in systemic exposure to odaterol. No dose adjustment is required for this combination.
In vitro studies have shown that odaterol does not inhibit CYP enzymes or drug transport proteins at the plasma concentrations achieved in clinical practice.
[Drug overdose]
The information on drug overdose with this compound is limited. Overdose studies with doses up to 5 μg/10 μg (tiotropium/odaterol) in patients with chronic obstructive pulmonary disease and up to 10 μg/40 μg (tiotropium/odaterol) in healthy subjects have been conducted with this combination formulation and no clinically meaningful effects were observed. Overdose may result in enhanced antimuscarinic-like effects of tiotropium and/or enhanced β2 receptor agonist effects of odaterol.
Symptoms
Overdose of the anticholinergic drug tiotropium
High doses of tiotropium may cause signs and symptoms associated with anticholinergic effects, such as decreased salivary flow, dry mouth/throat, and dry nasal mucosa.
Overdose of the beta2-receptor agonist odaterolOdaterol overdose may result in enhanced effects characteristic of beta2-adrenergic agonists, namely myocardial ischemia, hypertension or hypotension, tachycardia, arrhythmia, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle cramps, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis .
Drug overdose management
Treatment with this compound should be discontinued. Support therapy and symptomatic treatment should be considered. In severe cases, hospitalization is indicated. Cardioselective beta-blockers can be considered, but must be used with great caution, as the use of beta-adrenergic receptor blockers may trigger bronchospasm.
[clinical trial]
Effects on cardiac electrophysiology
Thiotropium (tiotropium):
In a QT-specific study performed in 53 healthy volunteers, administration of 18 μg and 54 μg of tiotropium inhalation powder (i.e., three times the therapeutic dose) over 12 days did not significantly prolong the QT interval in ECG.
Odaterol:
A double-blind, randomized, placebo- and active drug (moxifloxacin)-controlled study evaluated the effect of odaterol on the ECG T/QTc interval in a total of 24 healthy male and female volunteers. Compared with placebo, single doses of 10, 20, 30 and 50 μg of odaterol showed a dose-dependent mean change in the QT interval relative to the baseline period between 20 minutes and 2 hours after administration, with increases ranging from 1.6 ms (10 μg of odaterol) to 6.5 ms (50 μg of odaterol), and the upper limit of the bilateral 90% confidence interval for all dose levels was less than 10ms.
In a subset of 772 patients included in a 48-week placebo-controlled phase III clinical trial, the effects of 5 μg and 10 μg doses of odaterol on heart rate and rhythm were assessed using 24-hour continuous recording of electrocardiograms (Holter monitoring). No dose-related or time-related trends or patterns in the mean magnitude of heart rate or premature beat changes have been observed. The change in the number of premature beats from the baseline period to the end of treatment did not show a meaningful difference between odaterol 5 μg, 10 μg, and placebo.
Tiotropium Odaterol Inhalation Spray:
Two 52-week randomized, double-blind trials of this combination included 5162 patients with chronic obstructive pulmonary disease. In the pooled analysis, the range of cases of subjects with corrected QTcF intervals (corrected by the Fridericia method) with change values >30 ms from the baseline period at 40 minutes after dosing on days 85, 169, and 365 was 3.1%, 4.7%, and 3.6% in the combination group, respectively. In contrast, the range of such subject cases in the odaterol 5 μg group was 4.1%, 4.4%, and 3.6%, respectively; and the range of such subject cases in the tiotropium 5 μg group was 3.4%, 2.3%, and 4.6%, respectively.
Clinical Efficacy and Safety
The Phase III clinical development program for this combination includes three randomized, double-blind trials.
(i) two identically designed, 52-week, parallel-group trials comparing this combination with tiotropium (tiotropium) 5 μg and odalterol 5 μg (1029 patients received this combination) (Trials 1 and 2).
(ii) A 6-week crossover trial comparing this combination with tiotropium 5 μg and odaterol 5 μg and placebo (139 patients received this combination) (trial 3).
In these trials, the products compared, tiotropium 5 μg, odaterol 5 μg, and placebo, were administered via the Nembutal ® inhaler.
patient characteristics
The 52-week global clinical trial (Trials 1 and 2) enrolled 5,162 patients, primarily male (73%), Caucasian (71%) or Asian (25%), with a mean age of 64.0 years. The mean FEV1 after bronchodilator use was 1.37 L (GOLD2 (50%), GOLD3 (39%), and GOLD4 (11%)). The mean β2-agonist response was 16.6% of the baseline value (0.171 L). Concomitant pulmonary therapeutic agents allowed included inhaled corticosteroids (47%) and xanthines (10%).
The 6-week clinical trial (trial 3) was conducted in Europe and North America. Of the 219 patients recruited, the majority were male (59%) and Caucasian (99%), with a mean age of 61.1 years. The mean FEV1 value after bronchodilator administration was 1.55 L (GOLD2 (64%), GOLD3 (34%), GOLD4 (2%)). The mean β2-agonist response was 15.9% of the baseline value (0.193 L). Pulmonary therapeutic agents allowed for concomitant application included inhaled corticosteroids (41%) and xanthines (4%).
on lung function
In a 52-week clinical trial, this combination given once daily in the morning significantly improved lung function within 5 minutes of the initial dose compared to tiotropium (tiotropium) 5 μg (mean increase in FEV1 of 0.137 L for this combination and tiotropium 0.058L for 5 μg (p<0.0001) and 0.125L for 5 μg of odaterol (p=0.16)).
In both studies, a significant improvement in FEV1AUC0-3h response and FEV1 trough response (the primary endpoint of pulmonary function) was observed with this combination after 24 weeks compared with tiotropium 5 μg and odaterol 5 μg (Table 1).
Table1:24weeks after this combination with tiotropium5μggroup, the Odaterol5μggroup of FEV1AUC0-3hresponse and FEV1difference of the trough response (test1and2))
FEV1AUC0-3h responseFEV1 Valley Response Experiment 1Test 2 Test 1Test 2 nmeann meann meann MeansThis compound is more effective than522 — 502 — 521 — 497 — Tiotropium5μg526 0.117L 500 0.103L 520 0.071L 498 0.050L Odatello5μg525 0.123L 507 0.132L 519 0.082L 503 0.088L Pre-treatment Baseline FEV1: Trial 1=1.16L; Trial 2=1.15L
For all comparisons p≤0.0001
Compared with tiotropium 5 μg and odalterol 5 μg, this combination resulted in enhanced bronchodilatory effects that persisted throughout the 52-week treatment period. This combination also improved morning and nighttime peak expiratory flow rate (PEFR) compared with tiotropium 5 μg and odaterol 5 μg, as documented by daily patient testing.
In a 6-week trial, this combination significantly increased the FEV1 response compared with tiotropium 5 μg, odaterol 5 μg, and placebo throughout the 24-hour dosing interval (p<0.0001, Table 2).
Table2::6weeks after continuous24hour dosing interval of this combination with tiotropium. size:9pt”>5μg, odaterol 5 μg and placebo for FEV1 /sub>(L) difference (test3)
n 3hour averagen 12hourly averageAverage over 24hours1Valley valueThis compound is more effective than138 138 Thiotropium5μg137 0.109 135 0.119 0.110 0.079 Odatello5μg138 0.109 136 0.126 0.115 0.092 Placebo135 0.325 132 0.319 0.2800.207 Pre-treatment baseline FEV1= 1.30L
1 Primary endpoint
For all comparisons, p<0.0001
n=number of patient cases
Hard to breathe
After 24 weeks (Trial 1 and Trial 2), the mean TDI lesion score in the combination group was 1.98 units, which was significantly improved compared with tiotropium 5 μg (mean difference 0.36, p=0.008) and odalaterol 5 μg (mean difference 0.42, p=0.002). A greater number of patients in the treatment group with this combination achieved clinically meaningful improvement in total TDI score (MCID value defined as at least 1 unit) compared with the tiotropium 5 μg group (54.9% versus 50.6%, p=0.0546) and the odaterol 5 μg group (54.9% versus 48.2%, p=0.0026).
Application of emergency drugs
Patients treated with this combination formulation used the emergency drug salbutamol less frequently during the day and night than patients treated with tiotropium 5 μg and odaterol 5 μg (compared with 0.97 daily daytime uses in the tiotropium 5 μg group and 0.87 daily daytime uses in the odaterol 5 μg group, the combination The mean daytime use of emergency medication in the formulation group was 0.76 times per day, p <0.0001; the mean nighttime use of emergency medication in the compounded group was 1.24 times per day, p <0.0001, compared with 1.69 times per day in the tiotropium 5 μg group and 1.52 times per day in the odataterol 5 μg group, Trials 1 and 2).
Overall patient rating
According to the Patients’ Overall Rating (PGR) scale, patients treated with this combination had greater self-rated improvements in respiratory status compared to patients treated with tiotropium 5 μg and odalterol 5 μg (Trials 1 and 2).
Acute exacerbation
Previous studies have shown that tiotropium 5 μg reduces the risk of acute exacerbation of chronic obstructive pulmonary disease by a statistically significant amount compared to placebo. Acute exacerbation of slow-onset lung in the 52-week pivotal trials (Trials 1 and 2) was included as an additional study endpoint. In the pooled data set, the proportion of patients with at least one acute exacerbation of moderate/severe chronic obstructive pulmonary disease was 27.7% in the treatment group of this combination and 28.8% in the tiotropium 5 μg group (p=0.39). These studies were not specifically designed to evaluate the effect of treatment on acute exacerbations of slow-onset lung.
A 1-year, randomized, double-blind, active-controlled, parallel-group clinical trial (trial 9) compared acute exacerbations of chronic obstructive pulmonary disease in this combination with the tiotropium 5 μg group. All respiratory drugs, such as fast-acting beta-agonists, inhaled corticosteroids and xanthines, were allowed as combination therapy, except anticholinergics, long-acting beta-agonists and combination formulations of these two drugs. The primary end point of the study was the annual incidence of acute exacerbations of moderate to severe chronic obstructive pulmonary disease (3939 patients treated with this combination and 3941 patients treated with tiotropium 5 μg).
Most patients were male (approximately 71.4%) and Caucasian (79.3%). The mean age was 66.4 years, the mean FEV1 after bronchodilator use was 1.187 L (standard deviation 0.381), and a history of clinically significant cardiovascular disease was present in 29.4% of patients.
No new side effects were identified after treatment with this combination in the 3939 patients with chronic obstructive pulmonary disease included in this trial; and the safety profile remained consistent with the data documented in the pivotal trial.
An acute exacerbation of chronic obstructive pulmonary disease was defined as “a combination of lower respiratory events or symptoms (exacerbation or new onset) associated with underlying chronic obstructive pulmonary disease lasting 3 days or more and requiring antibiotics and/or systemic corticosteroids and/or hospitalization”.
Compared with tiotropium 5 μg treatment, treatment with this combination resulted in a further 7% reduction in the annual incidence of acute exacerbations of moderate to severe chronic obstructive pulmonary disease (rate ratio (RR) of 0.93, 99% confidence interval (CI), 0.85-1.02, p=0.0498). The study was designed with a significance level of 1%.
This combination therapy reduced the annual incidence of hospitalization due to acute exacerbation of chronic obstructive pulmonary disease by 11% compared with treatment (RR 0.89, 95% CI 0.76-1.03, p=0.1265). In addition to this, combination therapy reduced the annual incidence of moderate to severe acute exacerbations requiring systemic corticosteroid therapy by 20% (RR 0.80, 95% CI 0.68-0.94, p=0.0068) and also reduced the annual incidence of moderate to severe acute exacerbations requiring both systemic corticosteroid and antibiotic therapy by 9% (RR 0.91, 95% Cl 0.83-1.00, p=0.0447). This combination therapy did not reduce the decreased incidence of moderate to severe acute exacerbations requiring antibiotic therapy only (RR 1.07, 95% CI 0.96-1.20, p=0.2062).
Time to all-cause death was used as a secondary end point in this trial. There was no significant difference in the risk of all-cause death between treatment with this combination and treatment with tiotropium 5 μg. In the present combination formulation group and the tiotropium 5 μg group, 36 and 32 deaths were identified during the actual treatment period (i.e., treatment period plus 1 day), respectively (risk ratio (HR) 1.09, 95% CI, 0.67, 1.75, p=0.7357), whereas 107 and 121 deaths were observed during the planned study period (381 days), respectively (HR 0.88, 95% CI , 0.68, 1.15, p=0.3485).
Analysis of this acute exacerbation clinical trial (trial 9) is shown in Table 3.
Table 3: Effect of treatment with this compound on acute exacerbations (test9)
Research(NThis compound formulation,Ntiotropium5)Study Endpoints
This compound formulationTiotropium5μgratiopvaluefor a period of1yearIIIbphase acute exacerbation study
(Treatment set:)
3939,3941)Annual incidence of acute exacerbations of chronic obstructive pulmonary disease
Moderate to severe0.90 0.97 RR 0.93 (0.85, 1.02)
99% CI 0.0498 Time to first acute exacerbation of chronic obstructive pulmonary disease
Moderate to severeNumber of patients with an incident:1746Number of patients with an incident:1777HR 0.95 (0.87, 1.03)
99% CI 0.1188 Annual incidence of hospitalizations due to acute exacerbations0.180.20RR 0.89 (0.76, 1.03)
95% CI0.1265Time to first hospitalization due to acute exacerbation of chronic obstructive pulmonary diseaseNumber of patients with incidents:450Number of patients with incidents:469HR 0.93 (0.82, 1.06)
95% CI0.2773Health-related quality of life
This combination reduced the total St. George’s Respiratory Questionnaire (SGRQ) score, thus suggesting an improvement in health-related quality of life. After 24 weeks of treatment, this combination significantly improved the mean of the total SGRQ score compared with tiotropium 5 μg and odaterol 5 μg (Table 4); improvements were seen in all sections of the SGRQ questionnaire scores. More patients in the treatment group of the present combination achieved a clinically meaningful minimum difference (MCID, defined as a reduction of at least 4 units from baseline) in the total SGRQ score than in the tiotropium 5 μg group (57.5% versus 48.7%, p=0.0001) and the odaterol 5 μg group (57.5% versus 44.8%, p<0.0001).
Table4:Treatment24week afterSGRQtotal score. family:Times New Roman”>
n mean number by treatment group
(change from baseline period)Difference with this compounded groupmean (pvalue)Total scoreBaseline period 43.5 This compound formulation979 36.7(-6.8) Tiotropium5μg954 37.9(-5.6)-1.23(p=0.025) Odaterol5μg954 38.4(-5.1)-1.69(p=0.002)n=number of patient cases
In two other 12-week, placebo-controlled clinical trials, the primary endpoint also included the total SGRQ score after 12 weeks as a measure of health-related quality of life.
In the 12-week trial, the mean SGRQ total score (primary endpoint) at week 12 was improved by -4.9 (95% CI: -6.9, -2.9; p<0.0001) and -4.6 (95% CI. -6.5, -2.6; p<0.0001). In a pooled analysis of 12-week trials, the proportion of patients with a clinically meaningful reduction in total SGRQ score (defined as a reduction of at least 4 units compared to baseline) at week 12 was higher in the combination group (52%) than in the tiotropium 5 μg group (41%; ratio 1.56 (95% CI: 1.17, 2.07), p=0.0022) and placebo group (32% ; ratio 2.35 (95% CI: 1.75, 3.16), p <0.0001).
At all trial visits in trial 9, the combination group improved the Chronic Obstructive Lung Assessment Test (CAT, an index of health-related quality of life) score compared with tiotropium 5 μg (corrected mean difference compared with tiotropium from -0.7 (95% CI (-1.0, -0.5) ) at day 90 to -0.4 (95% CI (-0.7, -0.1) ), all p<0.01). In the responder analysis, a higher proportion of patients in the compounded group showed clinically meaningful improvement in CAT (defined as a decrease of ≥2 points) than in the tiotropium 5 μg group (44.51% and 40.77%, respectively, ratio 1.165, 95% CI 1.064-1.276, p<0.001).
deep inspiratory volume, respiratory distress and exercise tolerance
In three randomized, double-blind trials, the effects of this compound on deep inspiratory volume, respiratory distress, and symptom-limited exercise tolerance in patients with chronic obstructive pulmonary disease were investigated.
(i) Two identically designed, 6-week crossover trials comparing the effects of this combination with tiotropium 5 μg, odalterol 5 μg, and placebo on the constant power bicycle examination (450 patients received this combination) (Trials 4 and 5).
(ii) A 12-week parallel group trial comparing the effects of this combination with placebo on the Constant Power Treadmill Examination (139 patients received this combination) and the Constant Speed Walk Examination (in a subset of patients) (trial 6).
After 6 weeks of dosing, the effect of titropium 5 μg (0.114 L, p<0.0001; trial 4, 0.088 L, p=0.0005; trial 5), odaterol 5 μg (0.119 L, p<0.0001; trial 4, 0.080 L, p=0.0015; trial 5) and placebo (0.244 L, p& lt;0.0001; trial 4, 0.265L, p<0.0001; trial 5), this combination significantly improved resting deep inspiratory volume at 2 hours post-dose compared with placebo (0.265L, p<0.0001; trial 5).
In Trials 4 and 5, after 6 weeks of treatment, the present compounding resulted in an increase in the duration of the constant power bicycle check compared with placebo (Trial 4: geometric mean duration of 454 seconds in the compounding group compared with 375 seconds in the placebo group (20.9% improvement, p<0.0001); Trial 5: geometric mean duration in the compounding group of 466 seconds compared with 411 seconds in the placebo group (13.4% improvement, p<0.0001).
In trial 6, after 12 weeks of treatment, the present combination resulted in an increase in the duration of the constant power bicycle examination compared with placebo (geometric mean duration of 528 seconds in the present combination group versus 464 seconds in the placebo group (13.8% improvement, p=0.021).
[Pharmacology and Toxicology
Pharmacological effects
This product is a combination of tiotropium bromide and odaterol.
Tiotropium bromide is a long-acting muscarinic receptor antagonist (LAMA) with similar affinity for M1-M5-type muscarinic receptors, which dilates the bronchi by competitively inhibiting acetylcholine and M3-receptor binding on respiratory smooth muscle. Tiotropium dissociates slowly from M3- receptors and has a significantly longer half-life than ipratropium bromide. In nonclinical in vitro and in vivo trials, tiotropium dosedependently prevented acetylcholine-induced bronchoconstriction and the effect lasted longer than 24 h. Tiotropium inhalation produced mainly local rather than systemic effects in the respiratory tract.
Odaterol is a long-acting β2-adrenoceptor agonist (LABA) with high affinity and selectivity for human β2-adrenoceptors, which binds and activates after local inhalation <0}{0>In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta2- adrenoceptors compared to beta1-adrenoceptors and 2299-fold greater agonist activity compared to beta3-adrenoceptors.<}88{> beta2-adrenoceptors in the airway, activating intracellular adenylate cyclase, mediating an increase in cyclic-3′,5′-phosphate adenosine ( β-adrenoceptors are divided into 3 subtypes, β1-adrenoceptors are mainly expressed in cardiac muscle, β2-adrenoceptors are mainly expressed in respiratory smooth muscle, and β3-adrenoceptors are mainly expressed in adipose tissue. Although the epinephrine receptors on respiratory smooth muscle are predominantly β2-type, odaterol has the potential to act on the heart because cardiac muscle also expresses β2-adrenergic receptors.
Toxicological studies
Titropium bromide
Genotoxicity: Tiotropium Ames test, V79 Chinese hamster cell mutagenicity test, human lymphocyte in vitro chromosome aberration test, in vitro primary rat hepatocyte in vitro DNA synthesis assay, and mouse micronucleus assay all showed negative results.
Reproductive toxicity: A reduction in luteal number and bedfellows was seen in rats inhaling tiotropium ≥78 μg/kg/d (approximately 35 times the clinically recommended daily inhalation dose based on body surface area), no such adverse effects were seen at the 9 μg/kg/d dose, and no significant effects on fertility indices were seen at doses up to 1689 μg/kg/d. No significant effects on fertility index were observed at doses up to 1689 μg/kg/d. In pregnant rats and rabbits, no embryo-fetal malformations were observed at 1471 μg/kg/d and 7 μg/kg/d (approximately 790 and 8 times the clinically recommended daily inhalation dose based on body surface area), respectively; in rats, a decrease in fetal resorption, litter size, litter size, births and mean body weight was observed at 78 μg/kg/d (approximately 40 times the clinically recommended daily inhalation dose based on body surface area). In rats and rabbits, no such toxic effects were observed at 5 and 95 times the recommended daily dose (9 and 88 μg/kg/d, respectively). Tiotropium bromide can be secreted into rat milk, but it is not known whether it is secreted into human milk.
Carcinogenicity: Tiotropium bromide was inhaled at 59 μg/kg/d for 104 weeks in rats, 145 μg/kg/d for 83 weeks in female mice, and 2 μg/kg/d for 101 weeks in male mice (30, 40, and 0.5 times the clinically recommended daily inhalation dose based on body surface area, respectively), and no significant carcinogenicity was observed.
Odaterol
Genotoxicity: The results of the Ames test and in vitro mouse lymphoma test for odaterol were negative. The increased incidence of erythrocyte micronuclei seen in rats after intravenous administration of odaterol may be related to the drug’s promotion of compensatory erythropoiesis, and it is unlikely that odaterol induced micronuclei formation at clinical exposure.
Reproductive toxicity: No significant effects on fertility were seen in male and female rats after inhalation of odaterol 3068 μg/kg/d (approximately 2322 times the AUC at the clinically recommended daily inhalation dose based on exposure). No teratogenicity was observed in pregnant rabbits inhaled with odaterol 1054 μg/kg/d (approximately 2731 times the AUC at the clinically recommended daily inhalation dose, based on exposure). Odaterol can be transported across the placental barrier in rats.
Odaterol, when administered by inhalation, was teratogenic in New Zealand rabbits at 2489 μg/kg/d (approximately 7130 times the AUC at the clinically recommended daily inhalation dose based on exposure), with abnormal enlargement or narrowing of the atria or ventricles, ocular malformations, and sternal abnormalities in fetuses; at 974 μg/kg/d (approximately 1353 times the AUC at the clinically recommended daily inhalation dose based on exposure) No significant reproductive toxicity was observed at a dose of 974 μg/kg/d (approximately 1353 times the clinically recommended daily inhaled dose of AUC). Odaterol and metabolites can be secreted into rat milk, and it is unclear whether they are secreted into human milk.
Carcinogenicity: In a 2-year carcinogenicity test, ovarian tract smooth muscle tumors were seen in female rats at 25.8 μg/kg/d and 270 μg/kg/d (approximately 18 and 198 times the AUC at the clinically recommended daily inhalation dose on an exposure basis) of odaterol; in male rats at 270 μg/kg/d (approximately 1,000 times the AUC on an exposure basis). The tumors were not seen in male rats at a dose of 270 μg/kg/d (approximately 230 times the AUC at the clinically recommended daily inhalation dose based on exposure).
In a 2-year carcinogenicity test in mice, uterine smooth muscle tumors and smooth muscle sarcomas were seen in female mice at an inhalation dose of odaterol ≥76.9 μg/kg/d (approximately 106 times the AUC at the clinically recommended daily inhalation dose based on exposure); male mice at 255 μg/kg/d (approximately 455 times the AUC at the clinically recommended daily inhalation dose based on exposure). No tumors were seen at the dose of 255 μg/kg/d (approximately 455 times the AUC at the clinically recommended daily inhalation dose).
Other β2-adrenoceptor agonist drugs also induced an increased incidence of smooth muscle tumors and smooth muscle sarcomas in the female rodent genital tract. The relevance of these findings to humans is unclear.
[Pharmacokinetics]
a. General Introduction
When tiotropium (tiotropium) and odaterol are co-administered by inhalation, the pharmacokinetic parameters of the two components are similar to those of each active ingredient when administered alone.
The pharmacokinetics of tiotropium and odaterol were linear over the therapeutic concentration range. After repeated once-daily inhalation dosing, tiotropium reached steady state on day 7. Once-daily inhalation administration of odaterol reached steady state after 8 days, with a 1.8-fold accumulation compared to a single dose.
b. General characteristics of the active ingredient after drug administration
absorption
Thiotropium: Urinary excretion data in young healthy volunteers following inhalation of the drug via the Nembutal® inhaler indicate that approximately 33% of the inhaled drug volume enters the body circulation. The absolute bioavailability of the oral solution was 2 to 3%. Studies have shown that peak blood concentrations of tiotropium are reached 5-7 minutes after inhalation via the Nembutal® inhaler.
Odaterol: Absolute bioavailability after inhalation of odaterol in healthy volunteers is estimated to be approximately 30%, whereas absolute bioavailability after administration of an oral solution is less than 1%. Peak blood concentrations of odaterol are usually reached after 10-20 minutes of inhalation via Nembutal®.
Distribution
The plasma protein binding of tiotropium is 72% and the volume of distribution is 32 L/kg. studies in rats have shown that tiotropium does not cross the blood-brain barrier to any meaningful desired concentration.
Odaterol has a plasma protein binding rate of approximately 60% and a volume of distribution of 1110 L. Odaterol is a substrate for P-gp, OAT1, OAT3, and OCT1 transporter proteins. Odaterol is not a substrate for the following transporter proteins: BCRP, MRP, OATP2, OATP8, OATP-B, OCT2, and OCT3.
Biotransformation
Thiotropium: The degree of metabolism is very low. This is demonstrated by the fact that 74% of the dose is excreted in the urine as a prototype drug following an intravenous drug injection. Tiotropium is an ester that is non-enzymatically catabolized to ethanol (N-methyl scopolamine alcohol) and acid (dithiophene hydroxyacetic acid), neither of which binds to muscarinic receptors. In vitro tests using human liver microsomes and human hepatocytes have shown that an additional portion of the drug (less than 20% of the intravenously administered dose) undergoes a process dependent on the oxidation of cytochrome P450 (CYP)2D6 and 3A4 and subsequent binding to glutathione to various phase II metabolites.
Odaterol is primarily metabolized via direct glucuronidation and O-demethylation of methoxy groups and subsequent conjugation reactions. Of the 6 identified metabolites, only the unconjugated demethylation product (SOM 1522) can bind to the β2-receptor; however, such metabolites remain undetectable in plasma after prolonged inhalation of recommended therapeutic doses or after doses up to 4 times the recommended dose. The cytochrome P450 isozymes CYP2C9 and CYP2C8, as well as CYP3A4, which has a negligible role, are involved in the O-demethylation of odaterol, while the uridine diphosphate glucosyltransferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 are all involved in the formation of odaterol glucosinolates.
elimination
Titropium: Total clearance in healthy volunteers was 880 mL/min. after intravenous administration of tiotropium was excreted primarily as a prototype via urine (74%). In patients with chronic obstructive pulmonary disease, 18.6% of the drug is excreted in the urine after steady-state inhalation administration, and the rest of the drug that is not absorbed in the intestine is excreted in the feces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating that the drug can be actively excreted into the urine. The effective half-life of tiotropium after inhalation administration in patients with chronic obstructive pulmonary disease ranges from 27-45 hours.
Odaterol: The total clearance of odaterol in healthy volunteers was 872 mL/min and the renal clearance was 173 mL/min.[14C]-Labeled odaterol recovered 38% of the radioactive dose in urine and 53% in feces after intravenous administration. After intravenous administration, 19% of the prototype drug of odaterol was recovered in urine. After oral administration, only 9% of the radioactivity was recovered in the urine (0.7% as odaterol prototype), while the majority (84%) was recovered in the feces. More than 90% of the dose was excreted within 6 and 5 days after intravenous and oral administration, respectively. After odaterol inhalation, the prototype odaterol was excreted in the urine by healthy volunteers at steady state for approximately 5-7% of the dose during the interdose period. Plasma concentrations of odaterol after inhalation administration decrease in a multiphasic manner with a terminal half-life of approximately 45 hours.
c. Patient Characteristics
Tiotropium: As with all drugs that are primarily excreted renally, the renal clearance of tiotropium in elderly patients decreases in relation to age (347 mL/min in patients with chronic obstructive pulmonary disease aged =65 years ). This does not result in a corresponding increase in AUC0-6,ss or Cmax,ss values.
Odaterol: A meta-analysis of pharmacokinetic data in a controlled clinical trial using 2 trials (including 405 patients with chronic obstructive pulmonary disease and 296 patients with asthma) demonstrated no need for dose adjustment for the effects of age, sex, and weight on systemic exposure to odaterol.
Ethnicity
Odaterol: Comparison of pharmacokinetic data between the Odaterol study and the study suggests a trend toward higher systemic exposure in Japanese and other Asians compared with Caucasians. No safety concerns were identified in the year-long study of odaterol (odaterol administered at doses up to twice the recommended therapeutic dose) in Caucasians and Asians.
Renal insufficiency
Titropium: Patients with chronic obstructive pulmonary disease (CLCR50-80 mL/min) with mild renal impairment had an AUC06 after once-daily inhalation of tiotropium at steady state compared with patients with normal renal function (CLcr>80 mL/min) ,ss was slightly elevated (1.8-30% increase), whereas Cmax,ss was similar. Total exposure was doubled (82% increase in AUC0-4h and 52% increase in Cmax) after intravenous administration of tiotropium in patients with moderate to severe renal insufficiency (CLCR<50mL/min) compared with patients with normal renal function, as has been confirmed by inhalation of dry powder after Blood concentrations were confirmed.
Odaterol: No clinically significant elevation in systemic exposure was found in patients with renal injury.
hepatic insufficiency
Titropium: Hepatic insufficiency is not expected to have any relevant effect on the pharmacokinetics of titropium. Tiotropium is primarily cleared by renal excretion (74% in young healthy volunteers), with a small amount converted to a nonpharmacologically active product in a simple nonenzymatic esterification.
Odaterol: There was no evidence of differences in the elimination or protein binding of odaterol between subjects with mild or moderate liver injury and their healthy controls. It has not been studied in subjects with severe liver injury.
[Storage].
Store airtight, not frozen.
Please store in a safe place out of reach of children!
[Packaging
Each box contains one Nembrex® inhaler and one medicine bottle, 60 sprays per bottle (30 medicinal doses).
The vial containing the solution is made of polyethylene/polypropylene with a polypropylene cap with a silicone seal. The vials are sealed in an aluminum cylinder.
[Expiration date
36 months.
Expiration date of use: 3 months from the insertion of the vial into the inhaler.
[Executive Standard
Imported drug registration standard: JX20180113
[Imported drug registration certificate number
HXXXXXXXX
[Manufacturer
Company name: Boehringer Ingelheim International GmbH
Address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany (Germany)
Manufacturing site: Boehringer Ingelheim Pharma GmbH & Co.
Production address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany (Germany)
Domestic Contact.
Shanghai Boehringer Ingelheim Pharmaceutical Co.
Address:1010 Longdong Avenue, China (Shanghai) Pilot Free Trade Zone
Postal Code: 201203
Tel/Product Service Hotline: 400-820-5907, 800-820-5907
Fax Number: (021) 5080 1530
Website: www.boehringer-ingelheim.com.cn