[Date of Approval]
Odaterol Inhalation Spray
Please read the instructions carefully and use under the direction of a physician
Warning: asthma-related deaths
Long-acting betaR2R-adrenergic receptor agonist (LABA) increases the risk of asthma-related death. A large placebo-controlled US study compared the addition of another long-acting betaR2Safety of R-adrenergic receptor agonist (salmeterol) or placebo with data showing an increase in asthma-related deaths in patients treated with salmeterol. This result with salmeterol is thought to be a LABA-like effect, and odaterol, the active ingredient in this product, is also a LABA. The safety and efficacy of this product in patients with asthma have not been established. There are no indications for this product in the treatment of asthma (see [Contraindications], [Precautions]).
[Drug Name].
Generic Name: Odatrol Inhalation Spray
Trade name: Striverdi® /Striverdi®
English Name: Olodaterol Inhalation Spray
Hanyu Pinyin: Aodateluo Xirupenwuji
[Ingredients
Active Ingredient: Aodateluo 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 EDTA, anhydrous citric acid, water for injection.
[Properties
This product is a clear, colorless liquid in an aluminum-cased plastic bottle.
[Indications
This product is indicated for the maintenance treatment of long-term bronchodilation in patients with chronic obstructive pulmonary disease (COPD, or slow-onset lung, including chronic bronchitis and/or emphysema).
[Specifications
Each vial of 60 sprays contains 2.7 μg of odaterol hydrochloride (equivalent to 2.5 μg of odaterol) per spray, and the concentration of the solution contains 0.248 mg/ml of odaterol hydrochloride (equivalent to 0.226 mg/ml of odaterol).
[Dosage]
This product is for inhalation only. The vial can only be inserted into a Nembrex ® inhaler and used only for that inhaler.
1 medication dose consists of 2 sprays of medication from the Nembutal® inhaler.
{0>Adults<}0{>Adults<0}
{0>The recommended dose is 5 microgram olodaterol given as two puffs from the Respimat inhaler once daily, at the same time of the day.< }75{>The recommended dose is Odaterol 5µg, inhaled through the Nembutal ® inhaler at the same time of the day, 2 sprays once daily. <0}
{0>The recommended dose should not be exceeded.<}0{>The recommended dose should not be exceeded. <}0}
{0> <}50{>elderly patients<0}{0>Elderly patients can use Striverdi Respimat at the recommended dose.<}92{>Elderly patients can use Striverdi Respimat at the recommended dose. <0}
{0>Hepatic impairment<}50{>Hepatic impairment<0}
{0>Patients with mild and moderate hepatic impairment can use Striverdi Respimat at the recommended dose.<}92{>Patients with mild and moderate liver injury may use this product at the recommended dose. <0}
{0>There are no data available for use of Striverdi Respimat in patients with severe hepatic impairment.<}92{>There is There are no data on the use of this product in patients with severe liver injury. <0}
{0>Renal impairment{0>Renal impairment =”color:purple; font-family:Times New Roman”><}50{>Renal impairment<}50{>Renal impairment<0}
{0>Renally impaired patients can use Striverdi Respimat at the recommended dose.<}93{>Patients with renal impairment can use this product at the recommended dose. <0}Patients with severe kidney injury have limited experience with this product.
{0>Paediatric population<}100{>
Pediatric patients<0}
There are no data related to the use of this product in pediatric patients (under 18 years of age).
U
Dosing
To ensure proper use of the medication, patients should be instructed by a physician or other healthcare professional on how to use their Nembrex®® inhaler.
{0>Adults<}0{>
Dosing instructions
Product Description: This product is an inhalation spray of Odatrol. Please read the medication instructions carefully before starting this product.
Only use this inhaler once a day. You will need to spray 2 sprays with each use.
If this product has not been used for more than 7 days, 1 spray should be released toward the ground first.
If the product has not been used for more than 21 days, repeat steps 4-6 under “Preparation for initial use of Nembutal® inhaler” until a spray is visible. Then repeat steps 4-6 three more times.
Do not touch the needle punches inside the clear base.
{0>How to care for your inhaler<}100{>How How to care for your Nemblix ® inhaler<0}
Patients{0>Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at least once a week.<} 100{>The nozzle, including the metal part inside the nozzle, needs to be cleaned with a damp cloth or wet paper towel at least once a week. <0}
{0>Any minor discoloration in the mouthpiece does not <}95{>Any minor discoloration in the mouthpiece does not affect the performance of your Striverdi Respimat inhaler.<}95{>Some slight discoloration on the nozzle will not affect the performance of the Nembrex® ® inhaler. <0}.
{0>If necessary, wipe the outside of your Striverdi Respimat inhaler with a damp cloth.<}95{>If necessary, wipe the outside of your Striverdi® inhaler with a damp cloth. sup>® inhaler housing with a damp cloth if necessary.
<0}When you need a new Ondatrol inhalation spray
The medication dose indicator shows the approximate amount of medication remaining.
When the drug dose indicator enters the red zone of the scale, be prepared to replace it with a new Ondatrol inhalation spray, when approximately 7 days of dosing (14 sprays) remain.
Once the drug dose indicator pointer reaches the end of the red scale, the Nembutal® inhaler automatically locks into place, indicating that there is no more dose to release. 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 or completely used.
Preparation for initial use of Nembutal® inhaler
Take off the transparent base
Keep the dust cap closed.
Press the safety catch while using your other hand to firmly pull off the clear base.
Insert medicine bottle
Insert the thin end of the vial into the Nemblix ® inhaler.
Place the Nembrex®® 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 Nembrex®® inhaler. Reinstalling the Clear base
Return the clear base to its original position until it clicks.
Do not disassemble the clear base again. Rotation
Keep the dust cap closed.
Make sure to rotate the base in the direction of the arrow shown on the label of the NIBEL® inhaler until it clicks (i.e., halfway through the rotation).
Open
Open the dust cap fully.
Pressing
Point the Nembrex® ® inhaler to the floor.
Press the medication release button.
Cover the dust cap.
Repeat steps 4-6 until you see a spray of water.
After seeing the water spray, repeat steps 4-6 three more times.
Now you are ready to start using your Nemblix® inhaler. These steps will not affect the medicinal dose provided by this product. After completing these preparatory steps, the product will provide you with 60 sprays (30 medicinal doses) of medication.
Everyday use
Rotation
Keep the dust cap closed.
Make sure to rotate the clear base in the direction indicated by the arrow on the label of the Nembella® inhaler until it clicks (i.e., halfway through the rotation).
Open
Open the dust cap fully open.
Pressing
Exhale slowly and fully.
Hold the end of the suction nozzle with your lips, but do not block the ventilation holes. Point the Nembutal® inhaler toward the back of the throat.
While inhaling slowly and deeply through your mouth, press the medication release button and continue to inhale slowly and as long as you can.
Hold your breath for 10 seconds or as long as you can.
Repeat the rotate, open, press steps for a total of 2 inhalation puffs.
Close the dust cap until the Nembrex®® inhaler is used again.
[Adverse effects
a) Summary of safety characteristics
The most common adverse reactions when the recommended dose is given are nasopharyngitis, dizziness, hypertension, rash, and arthralgia. These reactions are usually mild or moderate.
b) Summary of Adverse Reaction Tables
The following incidence of adverse reactions is based on the approximate incidence of adverse drug reactions (ie, events related to odaterol) observed in the odaterol 5 μg dose group (1035 patients) from the pooled results of 6 placebo-controlled, parallel-group clinical trials conducted in patients with chronic obstructive pulmonary disease over a treatment period of 4 to 48 weeks.
Incidence was defined using the following conventions: very common (≥1/10); common (≥1/100 to <1/10); occasional (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and unclear (based on available data impossible to assess).
{0>System Organ Class / MedDRA Preferred Term<}0{>System Organ Class / MedDRA Preferred Term<0}{0>Frequency<}0{>Occurrence<}0{>UUU{0> Infections and infestations<}100{>Infections and Infectious Diseases<0} {0>Nasopharyngitis<}67{>Nasopharyngitis<0}{0>Uncommon<}0{>Uncommon<0} {0>Nervous system disorders<}100{>Nervous system disorders<0} {0> Dizziness<}67{>Dizziness<0}{0& gt;Uncommon<}100{>Occasional<0} {0>Vascular disorders<}100{>Vascular disorders<0} {0>Hypertension<}67{>hypertension<0}{0>Rare<}0{> ;Rare<}0 {0>Skin and subcutaneous tissue disorders<}82{>Skin and Subcutaneous tissue disorders<0} Rash{0>Uncommon <}100{>Eventually <0} {0>Musculoskeletal and connective tissue disorders<}100{>Musculoskeletal and connective tissue disorders<0} {0>Arthralgia<}67{>Arthralgia<0}{0>Rare<}100{& gt;Rare<0} c) Description of selected adverse reactions<0}
{0><}97{>The occurrence of a rash may be considered a hypersensitivity reaction to this product; as with all locally absorbed drugs, other hypersensitivity reactions may also occur. <0}
d) Beta2-agonist adverse reaction profile
{0><}90{> This is one of the long-acting beta2-adrenergic receptor agonist class of therapeutic agents. <0}{0> <}100{> Therefore, the occurrence of adverse reactions associated with β2-adrenergic receptor agonist drugs such as tachycardia, arrhythmia, palpitations, myocardial ischemia, angina pectoris, hypertension or hypotension, tremor, headache, nervousness, insomnia, dizziness, dry mouth, nausea, muscle cramps , fatigue, generalized weakness, hypokalemia, hyperglycemia, and metabolic acidosis. <0}
Reporting of suspected adverse reactions
It is important to continue to report suspected adverse reactions after a drug has received marketing authorization. This allows for ongoing monitoring of the benefit/risk balance of the drug. Healthcare professionals are urged to report any suspected adverse reactions to national health regulators through a viable reporting route.
[Contraindication
This product is contraindicated in patients who are hypersensitive to odaterol or to any of the excipients of this product.
All LABAs are contraindicated in patients with asthma who are not on long-term asthma control medications (see [Precautions]). This product is not indicated for the treatment of asthma.
[Precautions].
Asthma
This product should not be used in patients with asthma. The long-term effectiveness and safety of odaterol for asthma treatment has not been studied.
Asthma-related deaths (see black box warning)
Data from a large placebo-controlled study in patients with asthma showed that long-acting betaR2R-adrenergic receptor agonists may increase the risk of asthma-related death. No data are available to determine whether long-acting betaR2R- Whether adrenergic receptor agonists increase mortality in patients with chronic obstructive pulmonary disease.
size:1pt”>R2R-adrenergic agonist (salmeterol) to standard asthma therapy versus the addition of placebo. There was an increase in asthma-related deaths in patients treated with salmeterol (13/13,176 in salmeterol-treated patients compared with 3/13,179 in placebo-treated patients; relative risk 4.37, 95% CI 1.25 – 15.34). The increased risk of asthma-related death is thought to be a consequence of long-acting betaR2R-adrenergic receptor agonists (including this product) class effects. Studies sufficient to determine whether asthma-related mortality is elevated in patients treated with this product have not been performed. The safety and efficacy of this product in patients with asthma have not been established. There are no indications for this product for the treatment of asthma (see [Contraindications]).
This product should not be used in patients with acute exacerbations of slow-onset lung, which may be a life-threatening condition. The use of this product in patients with acute exacerbations of slow-onset lung has not been studied. Use of this product in such a situation is not appropriate.
This product should not be used for acute symptom relief, i.e., not as emergency treatment for an acute exacerbation of bronchospasm. The use of this product has not been studied in acute symptom relief and additional doses should not be used for this purpose. Acute symptoms can be treated with inhaled short-acting beta2-agonists.
When initiating treatment with this product, patients who have received inhaled short-acting β2-agonists on a regular basis (eg, 4 times daily) should be advised to discontinue the routine use of these drugs and to use them only for the relief of acute respiratory symptoms. When prescribing this product, healthcare providers should also prescribe inhaled short-acting beta2-agonists and instruct patients how to use them. Increased use of inhaled beta2-agonists is a sign of acute worsening of the disease that requires immediate medical attention.
Chronic obstructive pulmonary disease can deteriorate rapidly within hours or slowly over days or longer. If this product does not continue to control the symptoms of bronchoconstriction, or if the patient’s inhaled, short-acting beta2-agonist effectiveness is diminished, or if the patient requires more short-acting beta2-agonists to be inhaled than usual, these may be signs of an acute exacerbation of the disease. In such cases, the patient and the chronic obstructive pulmonary treatment regimen should be immediately re-evaluated. Increasing the daily dose of this product and exceeding the recommended dose in this situation is inappropriate.
Overdose and combination with long-acting beta2-agonists
As with other inhaled drugs containing β2-adrenergic drugs, this product should not be used more frequently than recommended, at higher doses than recommended, or in combination with other drugs containing long-acting β2-agonists, because the combination can lead to overdose. Clinically significant cardiovascular effects and death have been reported in association with overdose of inhaled sympathomimetic drugs.
Comorbidities
As with other sympathomimetic drugs, this product should be used with caution in patients with convulsive disorders or thyrotoxicosis, those who have or are suspected of having a prolonged QT interval, and those with an abnormal response to sympathomimetic amines. Intravenous administration associated with the beta2-agonist salbutamol has been reported to exacerbate established diabetes mellitus and ketoacidosis.
{0> <}100{> acute bronchospasm<0}
This product is used as once-daily bronchodilator maintenance therapy and should not be used to treat acute episodes of bronchospasm, i.e., not for emergency treatment.
{0><}100{>hypersensitivity reactions<0}
{0><}95{> Tachyphylaxis, including angioedema, may occur after administration of this product. If such reactions occur, discontinue treatment with this product immediately and consider switching to other alternative treatments. <0}
{0> <}100{>paradoxical bronchospasm<0}
{0><}94{>As with other inhaled drugs, this product may cause potentially life-threatening paradoxical bronchospasm. <0}{0><}94{>If paradoxical bronchospasm occurs, discontinue this product immediately and switch to other alternative therapy. <0}
{0> <}100{>Systemic effects<0}
{0><}79{>}Long-acting beta2-adrenergic agonists should be used with caution in all of the following patients: patients with cardiovascular disease, especially ischemic heart disease, severe compensatory cardiac dysfunction, arrhythmias, hypertrophic obstructive cardiomyopathy, hypertension, and aneurysms; patients with convulsive disorders or hyperthyroidism. Patients with known or suspected prolonged QT interval (e.g., QT > 0.44 seconds); and patients with abnormal reactions to sympathomimetic amines. <0}
<}100{>The following patients were excluded from the clinical trial: patients with a history of myocardial infarction within the previous year, unstable or life-threatening arrhythmias, hospitalization due to heart failure within the previous year, or a diagnosis of paroxysmal tachycardia (>100 beats/min). <0}{0><}100{> therefore, there is limited experience with these patient populations. <0}{0><}93{> This product should be used with caution in these patient populations. <0}
<}100{>Cardiovascular effects<0}
{0><}100{>Like other beta2-adrenergic agonists, odaterol may produce clinically significant cardiovascular effects in some patients, as evidenced by increased pulse rate, blood pressure measurements, and/or increased symptoms. <0}{0><}100{> Once these effects occur, discontinuation of the drug may be required. <0}{0><}100{> In addition, beta-adrenergic agonists have been reported to induce electrocardiographic (ECG) changes, such as T-wave hypoplasia and ST-segment depression, but the clinical significance of these observations is unclear. <0}
{0><}100{>hypokalemia<0}
{0><}100{>β2-adrenergic receptor agonists may cause significant hypokalemia in some patients and may result in cardiovascular adverse effects. <0}{0><}100{> The decrease in serum potassium is usually transient and does not require potassium supplementation therapy. <0}{0><}97{> In patients with severe chronic obstructive pulmonary disease, hypokalemia may be exacerbated by hypoxia as well as comorbid therapy (see [Drug Interactions]), which may increase the patient’s susceptibility to arrhythmias.
In clinical trials, clinically significant reductions in blood potassium associated with long-term use of this product were rare and occurred at a rate similar to that of placebo controls. <0}
{0><}100{>hyperglycemia<0}
Inhalation of high doses of beta2-adrenergic receptor agonists may increase blood glucose levels.
In clinical trials, clinically significant changes in blood glucose associated with long-term use of this product were rare and occurred at a rate similar to that of placebo controls. The use of this product in patients with poorly controlled diabetes has not been studied.
Anesthesia
Due to the increased susceptibility to cardiac adverse reactions with beta-agonist bronchodilators, this product should be used with caution if surgery is planned with halothane anesthetics. <0}
Effects on the ability to drive and manipulate machinery
<}100{> No studies have been performed on the effects of this product on the ability to drive and maneuver machinery. <0}
<}100{> However, patients should be advised that dizziness has been reported in clinical trials. <0}{0><}100{> Therefore, caution is advised when driving a vehicle or manipulating machinery. <0}{0><}100{> If patients experience dizziness, they should avoid potentially dangerous tasks, such as driving or manipulating machinery.
[For pregnant and lactating women].
Pregnancy
There are no data on the use of this product in pregnant women.
Animal studies have not shown direct or indirect harmful effects of reproductive toxicity in terms of clinically relevant exposures (see toxicology studies).
As a precautionary measure, it is best to avoid this product during pregnancy.
Like other beta2-adrenergic agonists, odaterol may inhibit labor because of its relaxing effect on uterine smooth muscle.
Lactation
There are no clinical data on the exposure of breastfeeding women to odaterol. It is not known if odaterol/metabolites are excreted through human milk. The pharmacokinetic/toxicological data available from studies in animals suggest that odaterol and/or its metabolites are excreted through breast milk.
Systemic exposure to odaterol/metabolites is negligible in breastfeeding females when the human dose is 5 μg per day, and therefore no relevant effects in breastfed neonates/infants are expected.
Decide whether to discontinue breastfeeding or discontinue/abandon treatment with this product, taking into account the benefit to the breastfeeding infant and the treatment benefit to the mother.
{0><}100{>Fertility<0}
{0><}92{>There are no clinical data available on the effect of this product on fertility. <0}Preclinical studies of odaterol have shown no adverse effects on fertility.
[Pediatric Dosage].
There are no data available regarding the use of this product in pediatric patients (under 18 years of age).
[Geriatric Use
Geriatric patients may use this product at the recommended dose.
[Drug Interactions].
Adrenergic drugs
Coadministration of other adrenergic drugs (the only combination therapy or part of a combination therapy) may potentiate adverse reactions to this product.
<}84{>xanthine derivatives, steroid hormones, or diuretics<0}
{0><}86{>The combined use of xanthine derivatives, steroid hormones, or nonpotassium-protective diuretics may potentiate the potassium-lowering effects of adrenergic agonists (see [Precautions]). <0}
Non-potassium-preserving diuretics
Beta-agonists can acutely worsen ECG changes and/or hypokalemia caused by nonpotassium-preserving diuretics (eg, cyclic or thiazide diuretics), especially when the recommended dose of beta-agonists is exceeded. Although the clinical significance of these effects is not known, caution is recommended when β-agonists are co-administered with non-potassium-preserving diuretics.
<}100{>β-blockers<0}
{0><}92{>β-adrenergic receptor blockers may impair or antagonize the effects of this product. <0}{0><}97{>Therefore, this product should be combined with beta-adrenergic receptor blockers (including eye drops) only if the combination is necessary. <0}{0><}100{> In such cases, cardioselective beta-blockers may be considered, but should still be administered with caution. <0}
{0> <}78{> monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, QTc interval prolonging drugs<0}
{0><}95{>Monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval may potentiate the effects of this product on the cardiovascular system. <0}
<}82{>Pharmacokinetic drug interactions<0}
No effects related to systemic exposure to odaterol were observed in drug interaction studies with coadministration of fluconazole (as a model inhibitor of CYP2C9).
Coadministration of odaterol with ketoconazole (as a potent P-gp and CYP inhibitor) increased systemic exposure of odaterol by approximately 70%. No dose adjustment was required for {0><}100{>. <0}
Coadministration of odaterol with tiotropium had no relevant effect on the systemic exposure of each of the two drugs.
In vitro studies have shown that odaterol does not inhibit CYP enzymes, and clinical practice has shown that odaterol does not inhibit drug transport protein concentrations in plasma.
[Drug overdose]
Symptoms
Overdose {0><}99{> Odaterol drug may cause the characteristic effects of enhanced beta2-adrenergic agonists, namely myocardial ischemia, hypertension or hypotension, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle cramps, nausea fatigue, generalized weakness, hypokalemia, hyperglycemia, and metabolic acidosis. <0}
Management of drug overdose
Treatment with this product should be discontinued. Perform supportive and symptomatic treatment. In severe cases, hospitalization is indicated. {0><}100{> Cardioselective beta-blockers may be considered, but extra caution must still be exercised, as the use of beta-blocker analogs may cause bronchospasm.
[Clinical trial].
{0> <}100{> effects on cardiac electrophysiology<0}
{0><}100{>A double-blind, randomized, placebo- and active drug (moxifloxacin)-controlled study in 24 healthy male and female volunteers evaluated the effect of odaterol on the electrocardiographic QT/QTc interval. <0}{0><}95{> Compared with placebo, the mean value of QT interval change relative to baseline period was dose-dependent between 20 minutes and 2 hours after administration of 10, 20, 30 and 50 µg single doses of odaterol, with increases between 1.6 ms (10 µg odaterol) and 6.5 ms (50 µg odaterol) , the upper limit of the bilateral 90% confidence interval for all dose levels of individually corrected QT (QTcI) was less than 10 ms. <0}
{0><}97{> The effects of 5µg and 10µg doses of this product on heart rate and cardiac rhythm were assessed using 24-hour continuous recording of electrocardiograms (Holter monitoring) in a subgroup including 772 patients in a 48-week placebo-controlled phase III clinical trial. <0}{0><}98{> No dose-related or time-related trends or patterns in the mean of the magnitude of heart rate or premature beat changes have been observed. <0}{0><}100{>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 5µg, 10µg, and placebo.
{0> <}100{>Clinical effectiveness and safety<0}
{0><}98{>The Phase III clinical trial of this product consisted of 4 pairs (8) of identically designed, randomized, double-blind, placebo-controlled clinical trials enrolling a total of 3533 patients with chronic obstructive pulmonary disease (1281 receiving a 5 μg dose and 1284 received a 10-μg dose):<0}
1. {0><}91{> Two 48-week placebo- and active drug-controlled, parallel-group trials of the same design with the active control drug formoterol 12 µg twice daily (Trials 1 and 2)<0}
2. {0><}88{>Two 48-week placebo-controlled, parallel-group trials of the same design (trials 3 and 4)<0}
3. {0><}100{>Two identically designed placebo- and active-drug-controlled, 6-week crossover-designed trials with the active control drug formoterol 12 μg twice daily (trials 5 and 6)<0}
4. {0><}100{> two placebo- and active drug-controlled, 6-week crossover-designed trials of the same design, with the active control drug being tiotropium bromide powder inhaler (Silvateam) 18 μg once daily (trials 7 and 8)<0}
{0><}100{> All studies included pulmonary function testing (1-second exertional expiratory volume, FEV1); the 48-week study assessed peak pulmonary function (AUC0-3) response and trough pulmonary function response were assessed, and the 6-week study assessed lung function performance between consecutive 24-hour dosing periods. <0}Two identically designed, placebo- and active drug-controlled, 48-week trials also included the Transitional Dyspnea Index (TDI) (as a measure of dyspnea) and the St. George’s Respiratory Questionnaire (SGRQ) (as a measure of health-related quality of life).
{0><}98{> Patients included in the Phase III clinical trial were: patients 40 years of age or older with clinically confirmed chronic obstructive pulmonary disease, a history of smoking for at least 10 pack years, and moderate to very severe pulmonary impairment (FEV after bronchodilator 1 less than 80% of normal expected value (GOLD class II-IV); FEV1/FVC (exertional spirometry) ratio less than 70% after use of bronchodilators). <0}
{0> <}100{> patient characteristics<0}
{0><}99{>The 48-week global clinical trials (Trials 1 and 2, Trials 3 and 4) enrolled 3104 patients, predominantly male (77%), white (66%) or Asian (32%), with a mean age of 64 years. <0}{0><}100{> The mean value of FEV1 after bronchodilator use was 1.38 L (GOLD II (50%), GOLD III (40%), GOLD IV (10%)). <0}{0><}93{>The mean value of the beta2-agonist response was 15% of the baseline value (0.160L). <0}{0><}99{> All pulmonary medications except other long-acting β2-agonists were allowed as combined therapy (e.g., tiotropium (24%), ipratropium (25%), inhaled glucocorticoids (45%), xanthines (16%)); included patients were stratified according to tiotropium use were stratified. <0}{0><}96{> In all four clinical trials, the primary efficacy endpoints of lung function were: change in FEV1 AUC0-3 relative to pretreatment baseline values and change in FEV1 trough values (before administration) relative to pretreatment baseline values (after 24 weeks for trials 1 and 2; and trials 3 and 4 after 12 weeks). <0}
<}100{> 6-week clinical trials (Trials 5 and 6, Trials 7 and 8) were conducted in Europe and North America. <0}{0><}100{>Trials 5 and 6 enrolled a total of 199 patients, most of whom were male (53%) and white (93%), with a mean age of 63 years. <0}{0><}100{> The mean FEV1 after bronchodilator use was 1.43 L (GOLD II (54%), GOLD III (39%), GOLD IV (7%)). <0}{0><}93{>The mean value of the beta2- agonist response was 17% of the baseline value (0.187L). <0}{0><}98{> All pulmonary agents were allowed as combined therapy except for other long-acting β2-agonists (e.g., tiotropium (24%), ipratropium (16%), inhaled glucocorticoids (31%), xanthines (0.5%)). <0}{0><}100{> Trials 7 and 8 included a total of 230 patients, most of whom were male (69%) and white (99.6%), with a mean age of 62 years. <0}{0><}100{> The mean FEV1 after bronchodilator use was 1.55 L (GOLD II (57%), GOLD III (35%), GOLD IV (7%)). <0}{0><}93{>The mean value of the beta2-agonist response was 18% of the baseline value (0.203L). <0}{0><}98{> All pulmonary medications were allowed as combination therapy except for other long-acting β2-agonists and anticholinergics (e.g., inhaled glucocorticoids (49%), xanthines (7%)). <0}
{0> <}100{>pulmonary function<0}
{0>In the 48 week trials, Striverdi Respimat, 5 micrograms administered once daily in the morning, provided significant improvement (p<0.0001) in lung function within 5 minutes following the first dose ( mean 0.130 L increase in FEV1 compared with a pre-treatment baseline of 1.18 L). <}99{>In a 48-week clinical trial, a 5-μg dose of this product, administered once daily in the morning, significantly improved lung function within 5 minutes following the first dose (P<0.0001) (mean FEV1 increase of 0.130 L compared with the pretreatment baseline value of 1.18 L). <0}{0>Significant improvement in lung function was maintained for 24 hours (mean 0.162 L increase in FEV1 AUC0-3 compared to placebo, p<0.0001; mean 0.071 L increase in 24 hour trough FEV1 compared to placebo, p<0.0001); the lung function improvements were evident in both tiotropium users and non-tiotropium users.<}100{>Significant improvements in lung function were maintained for 24 hours (FEV1AUC compared to placebo 0-3 increased by a mean of 0.162 L, P<0.0001; 24-hour FEV1 trough increased by a mean of 0.071 L, P<0.0001, compared with placebo); improvements in lung function were significant in both tiotropium users and non-tiotropium users. <0}The magnitude of the bronchodilatory effect of odaterol (FEV1 AUC0-3 response) was dependent on degree of baseline airflow limitation reversibility (tested with short-acting β-agonist bronchodilator administration); patients with a higher degree of baseline reversibility typically show a higher response to odaterol bronchodilator than patients with a lower degree of baseline reversibility. The bronchodilatory effect (measured as L) was lower in patients with more severe chronic obstructive pulmonary disease with odaterol and the active control drug. The bronchodilatory effect of this product was maintained during 48 weeks of treatment. {0>Striverdi Respimat also improved morning and evening PEFR ( peak expiratory flow rate) as measured by patient’s daily recordings compared to placebo.<}97{>The product similarly improved morning and nighttime peak expiratory flow rate (PEFR) compared to placebo based on the patient’s daily recordings. <0}
In the 6-week trial, this product showed a significantly higher FEV1 response (p<0.0001) during the complete 24-hour dosing interval compared to placebo (FEV1 AUC0-30.175 L (trials 5 and 6) and 0.211 L (trials 7 and 8) on average, p<0.0001; FEV1 AUC0-24 0.137 L (trials 5 and 6) and 0.168 L (trials 7 and 8) on average compared with placebo, p<0.0001; FEV1 AUC0-24 0.137 L (trials 5 and 6) and 0.168 L (trials 7 and 8) on average compared with placebo compared with a mean increase in 24-hour FEV1 trough of 0.102 L (trials 5 and 6) and 0.134 L (trials 7 and 8), p<0.0001). Improved lung function was associated with a mean increase in FEV1 AUC0-3 of 0.205 L with twice-daily formoterol (trials 5 and 6; mean increase in FEV1 AUC0-3 compared with placebo; mean increase in 24-hour FEV1 trough of 0.108 L compared with placebo (p<0.0001)) and once-daily tiotropium ammonium bromide powder inhaler (Servial) (Trials 7 and 8; mean increase in FEV1 AUC0-3 of 0.211 L compared with placebo; mean increase in 24-hour FEV1 trough of 0.129 L compared with placebo (p<0.0001)) were comparable.
{0> <}94{> dyspnea, health-related quality of life, emergency medication use, overall patient score<0}
{0>The Transition Dyspnea Index (TDI) and the St. George’s Respiratory Questionnaire (SGRQ) were also included in the replicate, placebo- and active-controlled, 48-week trials [Trials 1 and 2]. <}76{>The Transitional Dyspnea Index (TDI) and the St. George Respiratory Questionnaire (SGRQ) were also included in the replicate, placebo- and active-controlled, 48-week trials [Trials 1 and 2]. and active drug-controlled clinical trials (Trials 1 and 2). <0}
After 24 weeks, there was no significant difference in TDI lesion scores between this product, formoterol, and placebo due to unexpected improvement in the placebo group in one study (Table 1); in a post hoc analysis of patients who discontinued the drug, the difference was significant between this product and placebo groups.
{0>Table 1: TDI focal score after 24 weeks of treatment<}0{>Table 1: TDI lesion scores after 24 weeks of treatment<}0}
{0> Treatment Mean<}100{>Treatment Mean<0}{0>Difference to Placebo<}100{>Difference to Placebo<0} {0>Mean (p-value)<}100{>Mean (p-value)<0}{0>Primary analysis<}0{>Primary analysis<0}{0>Placebo<}100{>Placebo<0}1.5 (0.2) {0& gt;Olodaterol 5 μg once daily<}100{>Olodaterol 5 μg once daily once<0} 1.9 (0.2)0.3 (p=0.1704) {0>Formoterol 12 μg twice daily<}100{>Formoterol 12 μg twice daily<0}1.8 (0.2)0.2 (p=0.3718){0>Post-hoc analysis<}0{>Post-hoc Analysis<}0}{0>Placebo<}100 {>Placebo<0}1.5 (0.2) {0>Olodaterol 5 μg once dailyOlodaterol 5 μg once daily<0}2.0 (0.2)0.5 (p=0.0270) {0>Formoterol 12 μg twice daily<}100{>Formoterol 12 μg twice daily<0}1.8 (0.2)1.8 (0.2)0.4 (p=0.1166){0>After 24 weeks, Striverdi Respimat significantly improved mean SGRQ total score compared to placebo ( Table 2); improvements were seen in all 3 SGRQ domains (symptoms, activities, impact). <}98{>After 24 weeks, the mean SGRQ total score was significantly improved compared to placebo ( Table 2); and improvements were seen in all 3 SGRQ domains (symptoms, activities, impact). activity, and impact) were improved. The number of patients in the this product treatment group with improvement in the total SGRQ score greater than the clinically meaningful minimum difference (MCID, 4 units) was greater than in the placebo group (50.2% versus 36.4%, P<0.0001 ). <0}
{0>Table 2: SGRQ total-scores after 24 weeks of treatment<}83{>Table 2: SGRQ after 24 weeks of treatment<}83{>Table 2: Total SGRQ score after 24 weeks of treatment<0}
{ 0>Treatment Mean (change from baseline)<} 73{>Treatment mean (change from baseline period)<0} {0>Difference to Placebo<}100{>Compared to Placebo difference compared to placebo<0}{0>Mean (p-value)<}100{>Mean (p-value)<0}{0>Total score <}100{>Total score<0} {0>Baseline<}100{>Baseline period<0}44.4 td style=”padding-top: 3px; padding-left: 7px; padding-right: 7px; border-top: none; border-left: none; border-bottom: solid 0.5pt; border-right : solid 0.5pt”>{0>Placebo<}100{>Placebo<0}41.6 (-2.8) {0>Olodaterol 5 μg once daily<}100{>Olodaterol 5 μg once daily<0}38.8 (-5.6)-2.8 (p=0.0034) {0>Formoterol 12 μg twice daily< ;}100{>Formoterol 12 μg twice daily<0}40.4 (-4.0)-1.2 (p=0.2009){0>Patients treated with Striverdi Respimat used less daytime and nighttime rescue salbutamol compared to patients treated with placebo.<}95{>Patients treated with this product had less daytime and nighttime rescue salbutamol compared to patients treated with placebo. <0}
{0>In each of the 48 week trials, patients treated with Striverdi Respimat perceived a greater improvement in their respiratory condition compared to placebo, as measured by a Patients Global Rating (PGR) scale.<}78{>In each of the 48-week clinical trials, the results of the Patients Global Rating (PGR) scale suggested that patients treated with this product The improvement in respiratory status was greater in patients treated with this product than in the placebo group. <0}
[Pharmacology and Toxicology
Pharmacological effects
Odaterol is a long-acting beta2-adrenoceptor agonist (LABA) with high affinity and selectivity for human beta2–adrenoceptors, which binds and activates < 0}{0>In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta2-adrenoceptors compared to beta 1-adrenoceptors and 2299-fold greater agonist activity compared to beta3-adrenoceptors.<}88{>Beta2-adrenoceptors in the airway sub>2-adrenoceptors activate intracellular adenylate cyclase, which mediates an increase in cyclic-3′,5’phosphate adenosine (cAMP) levels, thereby relaxing airway smooth muscle and relaxing bronchioles, with effects lasting more than 24 h. Beta-adrenoceptors are divided into 3 subtypes, with beta1-adrenoceptors expressed mainly in cardiac muscle, beta2-adrenoceptors expressed mainly in 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 adrenergic 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
Genotoxicity: The results of the Ames test and in vitro mouse lymphoma test with odaterol were negative. The increased incidence of erythrocyte micronuclei seen after intravenous administration of odaterol in rats 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 inhaled with odaterol 3068 μg/kg/d (approximately 2322 times the recommended daily human inhalation dose on an AUC basis). No teratogenicity was observed in pregnant rabbits at 1054 μg/kg/d (approximately 2731 times the recommended human daily inhalation dose at AUC). Odaterol can be transported across the placental barrier in rats. Odaterol and metabolites are secreted into rat milk, and it is not clear whether they are secreted into human milk.
Pregnant New Zealand rabbits inhaled 2489 µg/kg/day of odaterol (approximately 7130 times the adult recommended maximum daily inhalation dose (ADI) on an AUC basis) had embryo-fetal developmental toxicity, with offspring having abnormal atrial or ventricular volumes, ocular malformations, abnormal sternal morphology, and cleft palate. These reactions are thought to be typical of the reproductive toxicity of high-dose β-adrenoceptor agonists in rodents; no such toxic reactions were seen in pregnant rabbits at a dose of 974 µg/kg/day (approximately 1353 times the adult recommended maximum daily inhaled dose on an AUC basis).
Carcinogenicity: In a 2-year carcinogenicity test, inhalation of 25.8 µg/kg/d and 270 µg/kg/d (approximately 18 and 198 times the recommended human daily inhalation dose on an AUC basis) of odaterol in female rats Ovarian tethered smooth muscle tumors were seen; no tumors were seen in male rats at a dose of 270 μg/kg/d (approximately 230 times the recommended human daily inhaled dose on an AUC basis).
In a 2-year carcinogenicity test in mice, uterine smooth muscle tumors and smooth muscle sarcomas were seen in female mice at an inhaled dose of odaterol ≥76.9 μg/kg/d (approximately 106 times the recommended human daily inhaled dose on an AUC basis); male mice at a dose of 255 μg/kg/d ( The tumors were not seen in male mice at a dose of 255 μg/kg/d (approximately 455 times the recommended human daily inhalation dose based on AUC).
Other β2-adrenoceptor agonist drugs also induce increased incidence of smooth muscle tumors and smooth muscle sarcomas in the reproductive tract of female rodents. The relevance of these findings to humans is unclear.
[Pharmacokinetics].
a) General description
{0>Information on the pharmacokinetics of olodaterol has been obtained from healthy subjects, COPD and asthma patients following oral inhalation of doses at and above the therapeutic dose. <}95{> Pharmacokinetics of olodaterol has been obtained from healthy subjects, COPD and asthma patients following oral inhalation of doses at and above the therapeutic dose.<0}.
{0>Olodaterol showed linear pharmacokinetics with a dose-proportional increase of systemic exposure after single inhaled doses of 5 to 70 microgram and multiple once daily inhaled doses of 2 to 20 microgram. <}100{>The pharmacokinetics of odaterol were linear with a dose-proportional increase of systemic exposure after single inhalation of 5 to 70 micrograms and multiple once daily inhalation of 2 to 20 micrograms.<0}.
{0>On repeated once daily inhalation steady-state of olodaterol plasma concentrations was achieved after 8 days, and the extent of exposure was increased up to 1.8-fold as compared to a single dose. <}100{>Repeated inhalations of olodaterol once daily achieved steady-state blood concentrations after 8 days, and the extent of exposure was increased up to 1. 8-fold as compared to a single dose. 8-fold.<0}
b) General characteristics of the active substance after drug administration
{0>Absorption<}100{>Absorption<0}
{0>Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. <}77{>Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation.<0}{0>In healthy volunteers the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30% whereas the absolute bioavailability was below 1% when given as an oral solution. <}99{>In healthy subjects the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30% whereas the absolute bioavailability was below 1% when given as an oral solution.<0} Therefore, the amount of odaterol available systemically after inhalation depends primarily on the amount of pulmonary absorption.
{0>Distribution<}100{>Distribution<0}
{0>Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. <}100{>Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration.<0}{0>The volume of distribution is high (1110 L), suggesting extensive distribution into tissue. <}94{>The volume of distribution is high (1110 L), suggesting extensive distribution into tissue.<0}{0>In vitro binding of [14C] olodaterol to human plasma proteins is independent of concentration and is approximately 60%. <}100{>In vitro, the binding of [14C]olodaterol to human plasma proteins is independent of concentration and is approximately 60%.<0}
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.
{0><}100{>biotransformation<0}
{0>Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. <}100{>Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation.<0} Of the six metabolites found, only the non-conjugated methylation product binds to the β2-receptor. however, this metabolite was not detected in plasma after long-term inhalation of the recommended therapeutic dose or after doses up to four times the recommended dose.{0>Olodaterol thus is considered the only compound relevant for pharmacological action. <}100{>Olodaterol thus is considered the only compound relevant for pharmacological action.<0}
{0>Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7 and 1A9 were shown to be involved in the formation of olodaterol glucuronides. <}100{>The cytochrome P450 isozymes CYP2C9 and CYP2C8, as well as CYP3A4, which plays a negligible role, are involved in the O-demethylation of olodaterol, while the uridine diphosphate glucosyltransferase isoforms UGT2B7, UGT1A1, 1A7 and 1A9 are all involved in the formation of olodaterol glucuronides.<0}
{0><}100{>eliminate<0}
{0>Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. <}100{>Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min.<0}
{0>Following intravenous administration of [14C]-labelled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in faeces. <}99{>[14C]-labelled olodaterol after intravenous administration, 38% of the radioactive dose was recovered in the urine and 53% was recovered in faeces.<0}{0>The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. <}100{>The amount of prototype olodaterol recovered in the urine after intravenous administration was 19%.<0}{0>Following oral administration, only 9% of the radioactivity (0. 7% unchanged olodaterol) was recovered in urine, while the major portion was recovered in faeces (84%). <}88{>After oral administration, only 9% (0. 7% of prototype odaterol) of the radiologically active agent amount was recovered, while most (84%) was recovered from feces.<0}{0>More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively. <}100{>More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively.<0}{0>Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5-7% of the dose. <}100{>After inhalation of odaterol, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for approximately 5-7% of the dose.<0}
Odaterol blood levels decrease in a multiphasic manner after inhalation, with a terminal half-life of approximately 45 hours.
{0>c) Patient characteristics<0}
{0>A pharmacokinetic meta-analysis was performed utilizing data from 2 controlled clinical trials that included 405 patients with COPD and 296 patients with asthma who received treatment with Striverdi Respimat. <}97{>A pharmacokinetic meta-analysis (Meta-Analysis) was performed utilizing data from 2 controlled clinical trials that included 405 patients with COPD and 296 patients with asthma who received treatment with Striverdi Respimat.<0}.
{0>The analysis showed that no dose adjustment is necessary based on the effect of age, gender and weight on systemic exposure in COPD patients after inhalation of Striverdi Respimat. <}97{>The analysis showed that no dose adjustment is necessary based on the effect of age, gender or weight on systemic exposure in COPD patients after inhalation of Striverdi Respimat. <0}.
{0> <}100{>renal insufficiency<0}
There was no clinically relevant increase in systemic exposure in patients with kidney injury.
{0> <}100{>hepatic insufficiency<0}
There was no evidence of differences in odaterol elimination between subjects with mild or moderate liver impairment and healthy controls, nor was there evidence of differences in protein binding. no studies were conducted in subjects with severe liver impairment.
{0><}100{>ethnicity<0}
{0>Comparison of pharmacokinetic data within and across studies revealed a trend for higher systemic exposure in Japanese and other “Asians” than in “Caucasians”. <}93{> Comparisons of pharmacokinetic data within and across studies revealed a trend for higher systemic exposure in Japanese and other “Asians” than in “Caucasians: purple; font-family:Times New Roman”><0}.
{0>No safety concerns were identified in clinical studies with “Caucasians” and “Asians” of up to one year with Striverdi Respimat at doses up to twice the recommended therapeutic dose.<}92{>No safety concerns have been identified in clinical studies of up to one year with Striverdi Respimat at doses up to twice the recommended therapeutic dose in “Caucasians” and “Asians.
[Storage].
Store airtight, not frozen.
Store in a safe place out of the reach of children!
[Packaging].
Each box contains one Nembutal® inhaler and one vial of 60 sprays (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.
Application period: 3 months from the insertion of the vial into the Nembrex® ® inhaler.
[Executive Standard
Imported drug registration standard JX20170310.
[Imported drug registration certificate number
HXXXXXXXX
[Manufacturer].
Company name: Boehringer Ingelheim International GmbH
Company address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany (Germany)
Manufacturing plant: Boehringer Ingelheim Pharma GmbH & Co.
Production address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany (Germany)
Domestic contact.
Boehringer Ingelheim Shanghai 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