What Is Indacaterol?

Indacaterol, trade name Indacaterol Inhalation Powder, is a chemical. Chemical name ( R ) -5- [2- (5,6-diethyldihydroinden-2-ylamino) -1-hydroxyethyl] -8-hydroxy- 1H -quinolin-2-one, The molecular formula is C ₂₄ H ₂₈ N ₂ O ₃ and the molecular weight is 392.49100. Indacaterol is an asthma drug (bronchodilator), and is mainly used in maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD).

Chinese name: Indacaterol
Foreign name: Indacaterol

CAS number: 312753-06-3
Molecular formula: C24H28N2O3
Molecular weight: 392.49100

Indaterol compounds

Indacaterol Basic Information

Chinese name indatrol

English name: indacaterol

English alias: 2 (1 H ) -QUINOLINONE, 5-[(1 R ) -2-[(5,6-DIETHYL-2,3-DIHYDRO-1H-INDEN-2-YL) AMINO] -1-HYDROXYETHYL] -8-HYDROXY-; Indacaterol; [3 H ] -Indacaterol;

CAS number: 312753-06-3

Molecular formula: C ₂₄ H ₂₈ N ₂ O ₃

Chemical structure:

Molecular weight: 392.49100

Exact mass: 392.21000

PSA: 85.35000

LogP: 3.53980 ^[1]

Indaterol drug profile

Indacaterol is a bronchodilator, belongs to the class of long-acting inhaled 2 receptor agonists (LABA), and is suitable for maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD). Production batch number H20120232 ^[2]

Indacaterol is effective for 5 minutes and lasts for 24 hours. This product is produced by Novartis Pharmaceuticals, Switzerland, and has been marketed in more than 70 countries and regions around the world since 2009. It was approved for listing in China by the State Drug Administration in June 2012. Its product name is Onbrez®, which is the first in China. Approved for use in the treatment of COPD for LABA-type single preparations.
Head-to-head clinical research data show that compared with salmeterol (an early drug of the LABA class), indacaterol can significantly improve the main clinical evaluation indicators of patients with moderate to severe COPD, and its safety and tolerability are good; Compared with tobromide (LAMA), indacaterol is equivalent in improving lung function in patients, and it is significantly better than tiotropium in alleviating dyspnea and improving quality of life.
[Common name] Indacaterol maleate inhalation powder [Product name] Angrun® / Onbrez® Breezhaler®
[English name] Indacaterol Maleate Powder for Inhalation
[Chinese Pinyin] Malaisuanyindateluo Xirufenwuji
[Indications] This product is a bronchodilator, suitable for maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD).

Indacaterol dosage

Dosage Recommended dose The recommended dose is to inhale the contents of a 150µg capsule once a day with Bishaler (Powder Inhaler). Increase the dose only as directed by your doctor.
This product should be used at the same time every day.
If the drug is missed once, it should still be taken at the same time the next day.
Hepatic impairment is not necessary for patients with mild to moderate hepatic impairment. There is no data on the application of this product in patients with severe liver damage.
Renal Impairment Patients with impaired renal function do not need to adjust the dose.
Usage is for inhalation only.
This product can only be inhaled using Bishaler (Powder Inhaler).
This product should not be taken orally.
[Specification] 150µg (based on C24H28N2O3)
[Validity] 24 months [Storage] Store at room temperature (10-30 ° C). Avoid mistaking by children. Keep the capsules in a blister just before use.
[Executive Standard] Import Drug Registration Standard JX20110174
[Ingredients]
The active ingredient of this product is indacaterol maleate.
Chemical name: ( R ) -5- [2- (5,6-Diethyldihydroinden-2-ylamino) -1-hydroxyethyl] -8-hydroxy- 1H -quinolin-2-one Chemical structure of maleate:
Molecular formula: C ₂₄ H ₂₈ N ₂ O ₃ · C ₄ H ₄ O ₄
Molecular weight: 508.56
[Character]
This product is a hard capsule for inhalation. Its content is white or off-white powder.
[Pharmacology and Toxicology]
Pharmacological effects Indacaterol is a long-acting 2-adrenergic receptor agonist.
Indacaterol acts locally as a bronchodilator in the lungs after inhalation. Although 2-receptors are the main adrenergic receptors in bronchial smooth muscle and 1-receptors are the main receptors in the heart, 2-adrenergic receptors also exist in the human heart, accounting for all of the adrenergic receptors. 10% to 50%. Although the exact function of these receptors is unknown, their presence suggests the possibility that even highly selective 2-adrenergic receptor agonists may have effects on the heart.

The pharmacological effects of 2-adrenergic agonist drugs, including indacaterol, are at least partly due to the activation of intracellular adenosine cyclase, which can catalyze the conversion of adenosine triphosphate (ATP) to cyclo-3 ' , Adenosine 5'-monophosphate (cyclic adenosine monophosphate). Increased cyclic adenosine monophosphate (cAMP) levels cause bronchial smooth muscle relaxation. In vitro studies have shown that the long-acting 2-adrenoceptor agonist indacaterol has a 24-fold higher agonistic activity on the 2-receptor than a 1-receptor and a 20-fold higher than the 3-receptor. The clinical significance of these findings is unknown.
Toxicology research

Genotoxicity: Indacaterol Ames test, V79 Chinese hamster cell chromosome aberration test and rat bone marrow micronucleus test results were all negative.
Reproductive toxicity: Indacaterol did not damage fertility in rats. Subcutaneous injection of indacaterol in rats and rabbits did not produce teratogenicity at doses up to 1 mg / kg, which were 130 times and 260 times (calculated as mg / m ² ) the human daily dose of 75ug.
Carcinogenicity: No significant increase in tumor incidence was observed in the carcinogenicity tests of transgenic mice given orally and by inhalation in rats. Rats were administered for life, and the incidence of benign ovarian leiomyoma and ovarian smooth muscle hyperplasia in female rats was increased, and the dose was about 270 times (calculated as mg / m ² ) of 75ug once a day in humans. CB6F1 / TgrasH2 hemizygous mice were orally administered indacaterol for 26 weeks at a dose of approximately 39,000 times the human daily dose of 75ug (calculated as mg / m ² ), showing no evidence of carcinogenesis

Other 2 adrenergic receptor agonists have also seen an increase in the incidence of genital leiomyomas in female rats, but the relevance of these findings to humans is not yet clear.

Pharmacokinetics

Indacaterol is a chiral molecule with an R-configuration.
Pharmacokinetic data comes from multiple clinical trials conducted in healthy volunteers and patients with COPD.

absorb

The median time to reach peak serum concentrations of indacaterol after single or multiple inhalation administration is approximately 15 minutes. Indacaterol's systemic exposure increases proportionally with dose (150µg to 600µg). After one dose, the absolute bioavailability of indacaterol is on average 43% to 45%. Systemic exposure comes from lung and intestinal absorption; about 75% of systemic exposure comes from lung absorption and the remaining 25% comes from intestinal absorption.

Indacaterol serum concentrations increased with repeated daily dosing. A steady state is reached within 12 to 14 days. The average accumulation rate of indacaterol between 150µg and 600µg once daily inhalation, that is, the 24-hour dosing interval AUC on the 14th day, compared with the first day of dosing, was in the range of 2.9-3.5.
distributed

After intravenous infusion, the indaterol distribution volume (Vz) was 2557 liters, indicating a widespread drug distribution. The in vitro binding rates to human serum and plasma proteins were 94.1% to 95.3% and 95.1% to 96.2%, respectively.
Biotransformation

In human ADME (absorption, distribution, metabolism, excretion) tests, after oral radiolabeled indacaterol, the prototype indacaterol is the main component in serum, accounting for about one-third of the total drug-related AUC in 24 hours. One. Hydroxyl derivatives are the most important metabolites in serum. Indacaterol O-glucuronide and hydroxylated indacaterol are secondary major metabolites. The diastereomers of the hydroxy derivative, the N-glucuronide indacaterol, and the C- and N-dealkane products have been identified as further metabolites.

In vitro studies have shown that only UGT1A1 subtypes in UGT metabolize indacaterol to phenol O-glucuronide. The formation of oxidative metabolites was observed in the co-incubation experiments of recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is considered to be the main isozyme of indacaterol hydroxylation. In vitro studies have further shown that indacaterol is a low affinity substrate for the efflux transporter P-gp.
Excretion <br In clinical trials with urine collection, urine-drained prototype indacaterol is usually less than 2% of the administered dose. The average renal clearance of indacaterol is between 0.46 and 1.20 liters / hour. Compared with indacaterol serum clearance of 23.3 liters / hour, renal clearance plays a smaller role in the systemic elimination of indacaterol (approximately 2% -5% of systemic clearance).
In a human ADME study in which indacaterol was administered orally, the fecal route was the main excretion route, more than the urine route. Indacaterol is excreted mainly into human feces in the form of a prototype parent drug (54% of the administered dose), followed by hydroxylated indacaterol metabolites (23% of the administered dose). 90% or more of the administered dose can be recovered from the excretion, and the material balance is reached.
Indacaterol's serum concentration showed a heterogeneous decline, with an average terminal half-life ranging from 45.5 to 126 hours. The effective effect half-life calculated from the indaterol accumulation rate after repeated dose administration was in the range of 40 to 52 hours, which was consistent with the time taken to reach a steady state of approximately 12 to 14 days.
Special Populations A population pharmacokinetic analysis showed that age (adult to 88 years), gender, weight (32-168kg), and ethnicity had no clinically significant effects on indacaterol pharmacokinetics. No differences were suggested between the ethnic subgroups.
In patients with mild to moderate hepatic impairment, there was no change in C _max or AUC of indacaterol, and there was no difference in protein binding rate compared with healthy subjects. Studies have not been conducted in subjects with severe hepatic impairment.
Because the contribution of the urinary pathway to systemic clearance is very low, studies have not been conducted in subjects with impaired renal function.

Indaterol interaction

Sympathomimetic drugs <br When combined with other sympathomimetic drugs (single or compound preparations), the adverse reactions of this product may increase.
This product should not be combined with other long-acting 2-adrenoceptor agonists or drugs containing long-acting 2-adrenoceptor agonists.
Hypokalogenic ₂ -adrenergic receptor agonists in combination with methylxanthine derivatives, steroids, or non-potassium-preserving diuretics may enhance the potential hypokalemia effect. Non-potassium-sparing diuretics, especially when used in excess of the recommended dose, may cause ECG changes or hypokalemia caused by taking non-potassium-sparing diuretics (such as tincture diuretics or thiazide diuretics). Although the clinical significance of these effects is unknown, it is recommended that this product be used in combination with non-potassium-preserving diuretics.
-adrenergic receptor inhibitors -adrenergic receptor inhibitors may reduce or antagonize the effects of 2-adrenergic receptor agonists. Therefore, unless there is an urgent need, this product should not be used in combination with -adrenergic receptor inhibitors (including eye drops). When needed, cardiac selective -adrenergic receptor inhibitors should be preferred, but caution should also be exercised use.
Monoamine oxidase inhibitors, tricyclic antidepressants, and drugs that extend the QTc interval. <br /> Indacaterol, like other 2-adrenergic receptor agonists, should be used with extreme caution when taking monoamine oxidase inhibitors, three Patients with cyclic antidepressants or other drugs known to extend the QTc interval because these drugs may enhance the effects of adrenergic receptor agonists on the cardiovascular system. Drugs known to extend the QTc interval may increase the risk of ventricular arrhythmias.
Metabolism and transporter drugs CYP 3A4 and P-glycoprotein (P-gp) can inhibit indacaterol clearance and increase the systemic exposure of indacaterol by a factor of two. The results of a 1-year clinical trial of this product, which is up to twice the recommended dose, have shown that the increased indaterol exposure due to drug interactions does not cause any safety issues.

Indaterol indication

This product is a bronchodilator, suitable for maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD).

Indacaterol adverse reactions

[Medication for pregnant and lactating women]
There are no data on the use of indacaterol in pregnant women. At clinical dose exposure levels, animal experiments have not shown direct or indirect adverse effects related to reproductive toxicity. Like other ₂ -adrenergic receptor agonists, indacaterol may inhibit the delivery process by relaxing the uterine smooth muscle. This product should only be used in pregnant women if the expected benefit is significantly greater than the potential risk.
Breastfeeding is not clear whether indacaterol and metabolites are secreted by human milk. Existing pharmacokinetic / toxicological data prove that indacaterol and metabolites can be secreted in animal milk. The risk of breastfeeding infants cannot yet be ruled out. The benefits of breastfeeding infants and breastfeeding women should be weighed to determine whether to stop breastfeeding or to discontinue treatment with this product.
Fertility has been observed to reduce pregnancy rates in rats. However, in the case of inhaled administration of the highest recommended dose, indacaterol is unlikely to have an effect on human reproduction or fertility.
[Child medication]
There is no information on the use of this product in children (under 18 years).
[Medicine for the elderly]
Although with age, maximum plasma drug concentrations and systemic exposures increase, elderly patients do not need to adjust the dose.
Adverse reactions
Safety summary The most common adverse reactions when using the recommended doses include nasopharyngitis (14.3%), upper respiratory infections (14.2%), cough (8.2%), headache (3.7%), and muscle spasms (3.5%). Most adverse reactions were mild or moderate, and the incidence of adverse reactions decreased as treatment continued.
The adverse reaction of COPD patients after inhalation of this product (recommended dose) is a systemic effect due to 2-adrenergic receptor activation, but it has no clinical significance. Mean heart rate changes were less than 1 per minute, tachycardia was rare, and the incidence was similar to placebo. Compared to placebo, drug-free QTcF was prolonged. Significantly longer QTcF intervals [eg,> 450ms for men;> 470ms for women] and the incidence of hypokalemia was similar to placebo. The mean maximum change in blood glucose was similar to placebo.
Summary of adverse reaction list A total of 4746 patients with moderate to severe COPD participated in the phase III clinical trial of this product. The maximum dose of indacaterol was 2 times the maximum recommended dose, and the longest treatment time was 1 year. Of these, 2611 patients used 150 µg once daily and 1157 patients used 300 µg once daily. Approximately 41% are patients with severe COPD. The average patient age was 64 years, of which 48% were older than or equal to 65 years, and most patients (80%) were white.
Table 1 summarizes the adverse reactions in the COPD safety database, which are named using the International Organized Medical Dictionary of Pharmacological Activities (MedDRA) system organ classification. In each system organ classification, the adverse reactions are categorized according to the following rules (CIOMS III) from highest to lowest incidence: very common (1 / 10); common (1 / 100, <1/10) ; Uncommon (1 / 1000, <1/100); rare (1 / 10000, <1/1000); very rare (<1 / 10,000), unknown (unable to accurately assess the incidence).
1 There have been reports of allergic reactions after the application of this product in the post-marketing experience. Because it is a spontaneous report from which the sample size cannot be determined, it may not be possible to reliably estimate the incidence or establish a causal relationship with drug exposure. Therefore the incidence is calculated based on clinical research experience.
When using 600 µg of this product once a day, its safety characteristics are generally comparable to the safety when using the recommended dose; the additional 1 adverse drug reaction is tremor (common).
Adverse reactions of concern During the phase III clinical trial visit, medical staff observed that an average of 17% to 20% of patients had a short cough within 15 seconds of inhaling the drug, usually for 5 seconds (currently about 10 seconds for smokers) ). It occurs more frequently in women than in men, and among smokers more than quitters. At the recommended dose, cough after inhalation is usually well tolerated, and no patients withdrew from the trial (cough is one of the symptoms of COPD disease, and only 8.2% of patients reported cough as an adverse event). There is no evidence that cough after administration is associated with bronchospasm, exacerbations, worsening disease, or poor efficacy.
Precautions
Asthma-related deaths Data from a large placebo-controlled trial in asthma patients show that long-acting 2-adrenergic receptor agonists may increase the risk of asthma-related deaths. There is no data to prove whether long-acting 2-adrenergic receptor agonists increase mortality in patients with COPD.
A 28-week, placebo-controlled study in the United States compared the safety of salmeterol (another long-acting 2-adrenergic receptor agonist) and placebo on the basis of conventional treatment for asthma. The number of asthma-related deaths increased in Romanian patients (13/13176 in salmeterol-treated patients and 3/13179 in placebo-treated patients; RR 4.37, 95% CI: 1.25, 15.34). The increased risk of asthma-related death is believed to be a class of effects of long-acting 2-adrenergic receptor agonists, including this product. There are insufficient studies to indicate whether this product increases asthma-related mortality when treated. The safety and effectiveness of this product in patients with asthma have not been clarified, so it is not suitable for the treatment of asthma.
Clinical trials of this product have reported severe asthma-related events, including death. These trials are not large enough to accurately quantify the difference in the incidence of severe asthma exacerbations between treatment groups.
Exacerbations and exacerbations When treating acute exacerbations of COPD that may be life-threatening, this product cannot be used as an initial treatment. This product has not been studied in patients with acute exacerbation of COPD. This product should not be used in this case.
This product should not be used to relieve acute symptoms, that is, it cannot be used for emergency treatment of bronchial spasms. Studies on the relief of acute symptoms with this product have not been conducted, and increasing doses cannot be used to relieve symptoms. Short-acting 2-adrenergic receptor agonists should be inhaled to treat acute symptoms.
When starting this product, patients who have been regularly using inhaled short-acting 2-receptor adrenaline agonists (for example, 4 times a day) should be instructed to stop using these drugs regularly, and only use these drugs when they need to relieve acute symptoms. When a doctor prescribes this product, a short-acting inhaled 2-adrenergic receptor agonist should be prescribed on the prescription, and the patient should be instructed on how to use it. Increasing the use of inhaled 2-adrenergic receptor agonists is a signal of exacerbation of the disease, prompting the need for timely medical attention.
COPD may deteriorate rapidly within a few hours, or it may deteriorate slowly over several days or longer. If this product cannot continue to control the symptoms of bronchospasm, or the patient's effectiveness of inhaling short-acting 2-adrenergic receptor agonists is reduced, or if the patient needs to inhale more short-acting 2-adrenergic receptor agonists than usual, these may be It is a sign that the disease is worsening. In this case, the patient and his COPD treatment plan should be re-evaluated immediately, and it should not be used in excess of the recommended daily dose of this product.
Excessive use of this product and combination with other long-acting 2-adrenergic receptor agonists are the same as other inhaled 2-adrenergic receptor agonists. The use of this product should not be too frequent and higher than the recommended dose, and cannot Long-acting 2-adrenergic receptor agonists are combined with other drugs, otherwise overdose may be caused. Clinically significant cardiovascular reactions and deaths associated with overuse of inhaled sympathomimetics have been reported.
Fast-onset allergic reactions may occur after applying this product. If you have an allergic reaction (especially difficulty breathing or swallowing, swelling of the tongue, lips and face, urticaria, rash), you should discontinue this product immediately and choose an alternative treatment.
Paradoxical bronchospasm. Like other inhaled ₂ -adrenergic receptor agonists, this product may cause life-threatening paradoxical bronchospasm. If paradoxical bronchospasm occurs, this product should be discontinued immediately and other alternative treatments should be selected.
Cardiovascular effects Like other ₂ -adrenergic receptor agonists, this product can produce clinically significant cardiovascular effects in some patients, with increased heart rate, increased systolic or diastolic blood pressure, or related symptoms. If the above reaction occurs, this product may need to be discontinued. In addition, beta-adrenergic receptor agonists have been reported to cause changes in the electrocardiogram (ECG), such as T wave depression, prolonged QTc interval, and decreased ST segment, but the clinical significance of these findings is unknown. Therefore, similar to other sympathomimetic amines, this product should be used with caution in patients with cardiovascular disease, especially coronary insufficiency, arrhythmia and hypertension.
Concurrent diseases are similar to other sympathomimetic amines. Patients with convulsive disease or thyroid syndrome, and patients allergic to sympathomimetic amines should use this product with caution. It has been reported that intravenous injection of a beta-adrenergic receptor agonist albuterol can aggravate existing symptoms of diabetes and ketoacidosis.
Hypokalemia and hyperglycemia ₂ -adrenergic receptor agonists may undergo intracellular shunting, leading to significant hypokalemia in some patients, which may lead to adverse cardiovascular reactions. Hypokalemia is usually transient and does not require supplementary treatment. Inhalation of high doses of 2-adrenergic receptor agonists may lead to elevated blood glucose.
In clinical trials of long-term administration of this product, clinically significant reductions in blood potassium or blood glucose changes are not common, and the incidence is similar to that of the placebo control group. This product has not been studied in patients with poorly controlled diabetes.
Impact on the ability to drive and operate the machine This product has almost no effect on the ability to drive and operate the machine.

Indacaterol safety

Concerns about the safety of indacaterol's LABAs, especially cardiovascular events, are mainly due to the announcement issued by the US FDA on February 18, 2010 restricting the use of LABAs alone in asthma patients. FDA's analysis of salmeterol (an early drug in the class of LABA) Multicenter Asthma Research Trial (SMART), Salmeterol National Surveillance Study (SNS), and a meta-analysis conducted by the FDA in 2008 found From the perspective, salmeterol has potential safety issues associated with exacerbation of asthma and an increased risk of death. Therefore, the FDA issued a notice requiring amendments to the labeling of LABAs for asthma and the development of a risk assessment and minimization plan (REMS) to regulate and restrict the use of LABAs in asthma patients (but COPD treatment is not restricted).
The FDA's subgroup analysis of salmeterol in asthma patients found that
1. The incidence of asthma-related deaths is higher in Caucasian (Caucasian) and African-American patients receiving salmeterol than in the placebo group (especially for African-American patients, with 27 new deaths per 10,000 people, and (Caucasian is 6; estimated to be related to medications used by patients of African descent). In addition, in the data analyzed by the FDA, no new deaths have been found in Asian, Hispanic and other groups.
2. Adolescents under 17 years old, especially children aged 4-11 years, are more likely to increase the risk of exacerbation of asthma due to salmeterol (compared with non-LABA group, the risk difference for patients aged 4-11 years is 15/1000)
In view of the fact that LABA alone is used to treat asthma due to FDA warning and concerns about drug cardiovascular events, the new generation of LABA indacaterol is focusing on safety data analysis (including the Chinese population) in the development. Especially in terms of cardiovascular, from the ECG, QTc interval, dynamic ECG monitoring and cardiovascular laboratory data, the incidence of adverse events was similar to the placebo group, and no safety issues related to indacaterol were found. In addition, since Indacaterol was launched overseas, as of the end of 2012, it has had more than 150,000 patient-years of experience; there are currently no reports of serious adverse events.

1. LABA: long-acting ₂ receptor agonist

2. LAMA: long-acting anticholinergic drugs