Indacaterol and glycopyrrolate

Uses

In Anesthesia:

• As a pre-operative antimuscarinic agent to reduce salivary, tracheobronchial and pharyngeal sections and to reduce the acidity of the gastric contents.
• As a pre-operative or intra-operative antimuscarinic to attenuate or prevent intraoperative bradycardia with the use of suxamethonium or due to cardiac vagal reflexes.
• To protect against the peripheral muscarinic actions of anticholinesterases such as neostigmine and pyridostigmine, used to reverse residual neuromuscular blockade produced by non- depolarising muscle relaxants.

In Peptic Ulcer:

For use in adults as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated.

Hyperhidrosis, Sialorrhea, Cerebral palsy.

Indacaterol is used for the treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol is a long-acting β2-adrenergic agonist used for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol and glycopyrrolate is also used to associated treatment for these conditions: Asthma, Chronic Obstructive Pulmonary Disease (COPD), Maintenance

How Indacaterol and glycopyrrolate works

Indacaterol works by stimulating adrenergic beta-2 receptors in the smooth muscle of the airways. This causes relaxation of the muscle, thereby increasing the diameter of the airways, which become constricted in asthma and COPD. It is also long acting due to its high affinity to the lipid raft domains in the airway membrane so it slowly dissociates from the receptors. Indacaterol also has a high intrinsic efficacy so it is also very rapid acting - onset of action occurs within 5 minutes.

The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown.

Dosage

Indacaterol and glycopyrrolate dosage

For IM/IV administration-

Pre-Anaesthetic Use:

• Adults:0.2 mg to 0.4 mg intravenously or intramuscularly before the induction of anesthesia. Alternatively, a dose of 0.004 to 0.005 mg/kg.
• Children (1 month to 12 years of age): 0.004 to 0.008 mg/kg up. Larger doses may result in profound and prolonged antisialogogue effect which may be unpleasant for the patient.

Intraoperative Use:

• Adults:A single dose of 0.2 to 0.4 mg (or 0.004 to 0.005 mg/kg) by intravenous injection should be used.
• Children: (1 month to 12 years of age) - A single dose of 0.004 to 0.008 mg/kg by intravenous injection should be used. This dose may be repeated if necessary.

Reversal of Neuromuscular Blockade:

• Adults:0.2 mg intravenously per 1 mg neostigmine or the equivalent dose of pyridostigmine.
• Children (1 month to 12 years of age) - 0.01 mg/kg intravenously with 0.05 mg/kg neostigmine or the equivalent dose of pyridostigmine. Supotaria may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.

For oral administration-

Initiate dosing at 0.02 mg/kg orally three times daily and titrate in increments of 0.02 mg/kg every 5-7 days based on therapeutic response and adverse reactions. The maximum recommended dosage is 0.1 mg/kg three times daily not to exceed 1.5-3 mg per dose based upon weight.

During the four-week titration period, dosing can be increased with the recommended dose titration schedule while ensuring that theanticholinergicadverse events are tolerable. Prior to each increase in dose, review the tolerability of the current dose level with the patient's caregiver.

Glycopyrrolate should be dosed at least one hour before or two hours after meals. The presence of high fat food reduces the oral bioavailability of Glycopyrrolate if taken shortly after a meal

Indacaterol capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of Indacaterol capsules are only for oral inhalation and should only be used with thedevice.

The recommended dosage of Indacaterol is the once-daily inhalation of the contents of one 75/150 mcg Indacaterol capsule using the device.

Indacaterol should be administered once daily every day at the same time of the day by the orally inhaled route only. If a dose is missed, the next dose should be taken as soon as it is remembered. Do not use Indacaterol more than one time every 24 hours.

Side Effects

Anticholinergic symptoms (mydriasis, hyperthermia, tachycardia, cardiac arrhythmia), Dry mouth, Dry skin, Anhidrosis, Flushing, Blurred vision, Cycloplegia, Photophobia, Palpitation, Xerophthalmia, Constipation, Urinary retention

The most commonly reported adverse effects were cough, nasopharyngitis, headache, nausea, oropharyngeal pain. Some other also reported of hypersensitivity reactions, paradoxical bronchospasm, tachycardia, pruritis and dizziness.

Toxicity

The expected signs and symptoms associated with overdosage of indacaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of indacaterol.

Precaution

Antimuscarinics should be used with caution (due to increased risk of side effects) in Down's syndrome, in children and in the elderly.

They should also be used with caution in gastro-esophageal reflux disease, diarrhea, ulcerative colitis, acute myocardial infarction, hypertension, conditions characterized by tachycardia (including hyperthyroidism, cardiac insufficiency, cardiac surgery) because of the increase in heart rate produced by their administration, coronary artery disease and cardiac arrhythmias, pyrexia (due to inhibition of sweating), pregnancy and breastfeeding.

Because of prolongation of renal elimination, repeated or large doses of glycopyrronium bromide should be avoided in patients with uremia.

Large doses of quaternary anticholinergic compounds have been shown to block end plate nicotinic receptors. This should be considered before using glycopyrrolate in patients with myasthenia gravis.

It is known that the administration of anticholinergic agents during inhalation anesthesia can result in ventricular arrhythmias.

Lactation: Excretion in milk unknown; use with caution

Rarely, serious (sometimes fatal) breathing problems have happened to people with asthma using a long-acting inhaled beta agonist (salmeterol). Since Indacaterol is similar to salmeterol, it might cause these serious breathing problems. Indacaterol has not been shown to be safe or effective to treat asthma and is not approved for this use.

Interaction

Decreases levodopa effects. Effects may be enhanced by using drugs with antimuscarinic properties or MAOIs concurrently. May antagonise the Gl effects of cisapride, metoclopramide and dompeidone.

Indacaterol shows interaction with Adrenergic Drugs, Xanthine Derivatives, Steroids, or Diuretics. Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of Indacaterol. The ECG changes or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by β2-agonists. Indacaterol, as with other β2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval. β-adrenergic receptor antagonists (beta-blockers) and Indacaterol may interfere with the effect of each other when administered concurrently.

Volume of Distribution

After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution.

Elimination Route

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

Half Life

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days.

Clearance

Renal clearance of indacaterol is, on average, between 0.46 and 1.2 L/h. Serum clearance of indacaterol is 18.8 L/h to 23.3 L/h.

Elimination Route

Renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol. In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose).

Pregnancy & Breastfeeding use

Pregnancy Category B. Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

Pregnancy Category C. There are no adequate and well-controlled studies with Indacaterol powder in pregnant women. Indacaterol powder should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known that the active component of Indacaterol powder, Indacaterol is excreted in human milk. Because many drugs are excreted in human milk and because Indacaterol has been detected in the milk of lactating rats, caution should be exercised when Indacaterol powder is administered to nursing women.

Contraindication

Angle-closure glaucoma; myasthenia gravis (large doses of quaternary ammonium compounds have been shown to block end plate nicotinic receptors); paralytic ileus; pyloric stenosis; prostatic enlargement. Anticholinesterase-antimuscarinic combinations such as neostigmine plus glycopyrronium should be avoided in patients with a prolonged QT interval.

All LABA are contraindicated in patients with asthma without use of a long-term asthma control medication. Indacaterol powder is not indicated for the treatment of asthma. Indacaterol is contraindicated in patients with a history of hypersensitivity to Indacaterol or to any of the ingredients.

Special Warning

Geriatric patients: No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renal impaired patients.

Hepatic impairment: No data are available for subjects with severe hepatic impairment.

Hepatic use: Not indicated for use in the hepatic impairment. Safety and efficacy have not been established.

Acute Overdose

The expected signs and symptoms associated with over dosage of Indacaterol powder are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an over dose of Indacaterol powder.

Storage Condition

Indacaterol capsules must always be stored in the blister, and only removed immediately before use. Keep in a cool & dry place. Keep out of the reach of children.

Innovators Monograph

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