Indacaterol

Indacaterol is a Bronchodilating agent belonging to the Pharmacological Class of Ultra Long-Acting Beta 2 Receptor Agonists (LABA).

Indacaterol is approved for treating COPD (Chronic Obstructive Pulmonary Disease), Chronic Bronchitis, and Emphysema.

Indacaterol reaches median peak concentration after 15 minutes of oral inhalation. Indacaterol has an extensive distribution of 2,361 L to 2,557 L.The prominent metabolites were found to be Phenolic O-glucuronides of Indacaterol and hydroxylated Indacaterol. Indacaterol is extensively excreted in feces when given orally.

The common side effects associated with Indacaterol include headache, increased thirst, increased urination, blurred vision, fever, flushing dry skin, difficulty in breathing, and fruit-like breath odor.

Indacaterol is available in the form of inhalation powder

Indacaterol is available in the U.S., Canada, U.K, E.U., Turkey, and Thailand

Indacaterol, belonging to the pharmacological class Ultra Long-Acting Beta 2 Adrenergic Receptor Agonist, acts as a Bronchodilator therapeutic agent (LABA).

Indacaterol acts via agonistic action on beta 2 adrenergic receptor which in turn stimulates adenyl cyclase following the conversion of ATP to cAMP. This in turn causes an increase in cAMP and leads to the relaxation of the smooth muscles in the airways.

Indacaterol causes bronchial smooth muscle relaxation, which is helpful in relieving the patient from COPD, Emphysema, or Chronic Bronchitis.

Indacaterol has an onset of action of 7.8±0.7 minutes, and the duration of action lasts up to more than 12 hours, approximately 24 hours. Indacaterol achieved Tmax 0.25 hours.

The inhalation powder is enclosed inside a hard gelatin capsule.

The capsule should be used with Neohaler Device only

The capsules should be used once a day after 24 hours time interval.

Steps to use:

• Cap is removed.
• The base of the inhaler is held and the mouthpiece is tilted to open the inhaler. A chamber can be seen
• The capsule is removed from the packaging and the capsule is kept inside the chamber.
• After the capsule is in place, the mouthpiece is clicked.
• A click sound can be heard if firmly pressed. Now take the fingers off the button.
• Move your head away from the inhaler and breathe out fully.
• Breathe deeply and steadily
• Remove the inhaler from your mouth while holding your breath for 5-10 seconds. Breathe out away from the inhaler.
• Make sure that you have taken your full dose, and check to see if there is any powder left in the capsule.
• Remove and discard the used capsule.

Indacaterol can be used to treat:

• Chronic bronchitis
• Emphysema
• Maintain airflow obstruction in patients suffering from Chronic Obstructive Pulmonary Disease.

Indacaterol acts on Beta-adrenergic receptors and stimulates them in order to cause relaxation of the smooth muscles in the Bronchioles.

Indacaterol is approved for use in the following clinical indications:

• COPD (Chronic Obstructive Pulmonary Disease)
• Chronic Bronchitis
• Emphysema

Indacaterol administration dose is 75 mcg inhaled once daily. Indacaterol is administered via neohaler only.

The duration and dosage of treatment should be as per the clinical judgment of the treating physician.

27.5 mcg, 75mcg,

European Agency approved dose: 150mcg, 300mcg

To maintain good respiratory health, smoking cessation is a must.

Diet containing refined and high energy-dense foods, red and processed meat, added sugar, salt, preservatives, low antioxidants and vitamins, low fiber, food with high glycemic index and saturated and trans fat food needs to be restricted.

The dietary restriction should be individualized as per patient requirements

Indacaterol may be contraindicated in the following conditions:

• Indacaterol is not indicated in the treatment of Asthma as a monotherapy (can be used along with inhaled corticosteroids)
• Indacaterol has been contraindicated in the patients with a history of Hypersensitivity towards Indacaterol or any ingredients of the medication.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Deterioration of Asthmatic Condition, including death:

There might be a deterioration of the asthma condition over a period of time. The increased usage of Indacaterol is a noted marker for the destabilization of the condition. Therefore a re-evaluation of the patient's condition should be considered, and the usage of anti-inflammatory agents such as corticosteroids should be considered. Serious asthma-related events, including deaths, have been reported in clinical trials.

• Deterioration of the acute and severe conditions of COPD:

Indacaterol should not be administered in the conditions of acute and severe COPD, as it might lead to a life-threatening condition.

In the acute symptoms of bronchospasm, Indacaterol should not be used. The use of short-acting beta 2 agonists should be considered in this situation.

While starting the administration of Indacaterol, the patients must be advised to withdraw the regular usage of short-acting beta 2 agonists and to only use it for symptomatic relief from acute respiratory symptoms.

During the episodes of the deterioration of the COPD condition, the use of Indacaterol must be withdrawn, and a re-evaluation of the patient's condition must be considered. The markers for the deterioration of the condition include an increased dose of Indacaterol or increased usage of Indacaterol or less effectiveness of the short-acting beta 2 agonists.

• Hypersensitivity events:

In the rare events of Hypersensitivity such as swelling of tongue, lips, and face, urticaria of the skin, difficulty in breathing or swallowing, rashes. Indacaterol should be withdrawn, and other alternate therapy must be considered.

• Paradoxical bronchospasm:

Paradoxical bronchospasm might be a life-threatening condition; therefore, Indacaterol should be immediately withdrawn during such a condition.

• Cardiovascular events:

Indacaterol has the potential of causing Myocardial Ischemia, Cardiac Arrest, changes in the ECG curve such as flattening of the T segment, prolongation of Q-Tc segment, and ST segment depression has been found to be associated with the beta 2 adrenergic agonist.

• Hypokalemia:

Indacaterol causes a decrease in potassium levels which potentially produces adverse cardiac events.

• Xanthine, Steroids, and Diuretics:

In acute asthma conditions, the use of Xanthine, Steroids, and Diuretics should be avoided or closely monitored as it may lead to hypoxia

• Diabetes Mellitus:

During Indacaterol usage, a patient with Diabetes Mellitus condition might suffer from hyperglycemia and will be unable to compensate in the condition of ketoacidosis

Indacaterol or the components of the medication have not been known to be excreted in milk.

Yet decision should be made by the treating physician whether to continue or discontinue this medication and should be only used if the benefits outweigh the risks.

There is no well-known, established data on Indacaterol use in pregnant women.

After subcutaneous administration of Indacaterol in rats and rabbits at doses up to 1 mg/kg, 130 and 260 times approximately, respectively, the 75 mcg dose on an mg/m2 basis, it was found that Indacaterol was not teratogenic.

Yet decision should be made by the treating physician whether to continue or discontinue this medication and should be only used if the benefits outweigh the risks.

The adverse reactions related to Indacaterol can be categorized as:

Common

• Fainting
• Fast or irregular heartbeat
• Sweating
• Tightness in the chest
• Troubled breathing
• Fever
• Nausea
• Arm, back, or jaw pain
• Chest pain or discomfort
• Chest tightness or heaviness
• Chills
• Cough
• Dizziness
• Sneezing
• Sore throat

Less Common

• Sweating
• Tingling of the hands or feet
• Unexplained weight loss
• Unusual tiredness or weakness
• Unusual weight gain
• Bloating or swelling of the hands, lower legs, feet, face, arms,
• Blurred vision
• Body aches or pain
• Increased urination
• Loss of consciousness
• Loss of voice
• Rapid weight gain
• Runny or stuffy nose
• Stomachache
• Vomiting
• Dry mouth
• Ear congestion
• Fainting
• Flushed, dry skin
• Fruit-like breath odor
• Headache
• Increased hunger
• Increased thirst

Rare

• Redness of the skin
• Troubled swallowing
• Racing heartbeat or fast irregular pounding.
• Hoarseness of voice
• Joint pain, stiffness, or swelling
• Hives, itching, skin rash
• Irritation

The clinically relevant drug interactions of Indacaterol are briefly summarized here:

• Monoamine Oxidase Inhibitors or Anti-Depressants: Patients should be monitored closely, or an alternate therapy must be considered while using Indacaterol as it might lead to some cardiovascular events in patients such as prolongation of QT-wave, cardiac arrhythmias, etc.
• Beta-blockers or Sympathomimetics: Indacaterol should not be concomitantly administered with the beta-blockers as it might worsen the patient's respiratory condition. In the condition of myocardial infraction use of cardioselective beta-blockers should be considered with caution.
• Diuretics: The use of loop diuretics and thiazide diuretics might worsen the condition of the patient under the treatment of Indacaterol, such as Hypokalemia and ECG changes
• Xanthine and Steroids: The use of Xanthines and Steroids along with Indacaterol might lead to Hypokalemia. Therefore caution is advised during concomitant use.

The common side effects of Indacaterol includes the following:

• Headache
• Increased thirst.
• Increased urination.
• Blurred vision.
• Fever.
• Flushed, dry skin
• Difficulty in breathing.
• Fruit-like breath odor.

The use of Indacaterol should be prudent in the following group of special populations:

• Pregnancy:

There is no well-known, established data on Indacaterol use in pregnant women.

During subcutaneous administration to rats and rabbits at doses up to 1 mg/kg, approximately 260 and 130 times, respectively, the 75 mcg dose on an mg/m2 basis, it was found that Indacaterol was not teratogenic.

Yet decision should be made by the treating physician whether to continue or discontinue this medication and should be only used if the benefits outweigh the risks.

• Labor and Delivery:

For Indacaterol use on preterm labor or labor at term, there were found to be no adequate and well-controlled human studies. Because there is a potential for beta-agonist interference with uterine contractility, the use of Indacaterol during labor should be restricted and should be used if only in whom the benefits clearly outweigh the risks.

• Breastfeeding Mothers:

Indacaterol or the components of the drug medication have not been known to be excreted in milk.

Yet decision should be made by the treating physician whether to continue or discontinue this medication and should be only used if the benefits outweigh the risks.

• Pediatric Use:

In pediatric patients, the safety and effectiveness of Indacaterol have not been established. Yet, Indacaterol is not indicated for use in children.

• Geriatric Use:

Based on available data, no adjustment of Indacaterol dosage in geriatric patients is warranted. Among the total number of patients who received Indacaterol at the recommended dose in the clinical studies of 75 mcg once daily from the pooled 3-month database, 239 were <65 years, 153 were 65–74 years, and 57 were ≥75 years of age.

There were no overall differences in effectiveness. In the 3-month pooled data, the adverse drug reaction profile was similar to the older population when compared to the patient population overall. When treated at higher doses (300 mcg and 600 mcg) over the course of a year, the adverse drug reaction profiles for patients >65 years were similar to that of the general patient population.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Indacaterol.

An increase in pulse rate, systolic blood pressure, and QTc interval was found in COPD patients after administering single doses of 40 times, the 75 mcg dose associated the expected signs and symptoms for e.g., nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, angina, hypertension or hypotension, tachycardia, hypokalemia, hyperglycemia, metabolic acidosis with heart rate up to 200 bpm, arrhythmias, nausea, dizziness, fatigue, malaise, and insomnia. With all inhaled sympathomimetic medications along with Indacaterol overdose, cardiac arrest and even death may be associated.

Treatment of overdosage consists of:

• Withdrawing of Indacaterol together with institution of appropriate symptomatic and supportive therapy.
• The use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm.
• Monitoring heart rate is recommended in cases of overdosage.

Pharmacodynamics

Indacaterol, belonging to the pharmacological class Ultra Long-Acting Beta 2 Adrenergic Receptor Agonist, acts as a Bronchodilator therapeutic agent.

Indacaterol acts via stimulating the beta 2 adrenergic receptor and causes relaxation of the smooth muscles in the airways and was recently approved for use in the United States. The duration of action of Indacaterol is approximately 24 hours, which allows once-in-a-day administration.

Pharmacokinetics

• Absorption:

Indacaterol achieved the median time to reach peak serum concentrations at approximately 15 minutes after single or repeated inhaled doses. The Absolute bioavailability of Indacaterol achieved an average of 43-45% after an inhaled dose.

• Volume of distribution:

Indacaterol, after intravenous infusion, achieved a volume of distribution (Vz) of about 2,361 L to 2,557 L, indicating that Indacaterol is extensively distributed.

• Protein binding:

Indacaterol in vitro human serum was found to be 94.1-95.3%, and plasma protein was found to be 95.1-96.2%.

• Metabolism:

After radio labeled Indacaterol was ingested orally, the main component in serum was found to be unchanged Indacaterol, which accounts for about one-third of total drug-related AUC over 24 hours. The most prominent metabolites in serum were the monohydroxylated derivative, glucuronide conjugate, and the 8-O-glucuronide. Other identified metabolites in the serum include C- N-dealkylated products,a diastereomer of the hydroxylated derivative, and an N-glucuronide of indacaterol. In the hydroxylation of Indacaterol, CYP3A4 is found to be the predominant isoenzyme responsible.

• Route of elimination:

Indacaterol was given orally in a human ADME study where the fecal route of excretion was dominant over the urinary passage. Renal clearance consists of about 2 to 6% systemic clearance to eliminate systemically available Indacaterol. The major primary route of elimination of Indacaterol was found in feces, as unchanged parent drug (54% of the dose) and hydroxylated Indacaterol metabolites (23% of the dose).

There are some clinical studies of the drug indacaterol mentioned below:

1. To Y, Kinoshita M,et.al. Assessing efficacy of indacaterol in moderate and severe COPD patients: a 12-week study in an Asian population. Respir Med. 2012 Dec;106(12):1715-21.

2. Gotfried MH, et al. Efficacy of indacaterol 75 μg once-daily on dyspnea and health status: results of two double-blind, placebo-controlled 12-week studies. COPD. 2012 Dec;9(6):629-36.

3. Kerwin EM, et al. Efficacy and tolerability of indacaterol 75 μg once daily in patients aged ≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies.

1.https://go.drugbank.com/drugs/DB05039

2.https://www.drugs.com/dosage/indacaterol.html

3.https://pubchem.ncbi.nlm.nih.gov/compound/Indacaterol#section=Use-and-Manufacturing

4.https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022383s002lbl.pdf