Indacaterol + Glycopyrronium + Mometasone Furoate
Indacaterol + Glycopyrronium + Mometasone Furoate Uses, Dosage, Side Effects, Food Interaction and all others data.
Glycopyrronium is a long-acting, specific antimuscarinic agent, in clinical medicine often called an anticholinergic. It has a similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, inhibition of M3-receptors at the smooth muscle results in relaxation. The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.
Glycopyrronium is a quaternary ammonium compound that is one of the most commonly prescribed long acting muscarinic antagonists. Glycopyrronium slowly dissociated from muscarinic receptors, leading to a long duration of action. It has a wider therapeutic index than other anticholinergic medications, such as tiotropium. Patients should be counselled regarding the risk of worsening urinary retention, risk of overheating, and transient blurred vision.
Indacaterol is a long acting β2-adrenergic agonist. It relaxes the bronchial smooth muscle by selective action on β2-receptor which acts locally in the lungs and with little effect on heart rate.
When inhaled, Indacaterol acts locally in the lung as a bronchodilator. The pharmacological effects of β2-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 monophosphate. Increased cyclic AMP levels cause relaxation of bronchial smooth muscle.
Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are β(2) -agonists and anticholinergics, either alone or in combination. Currently available β(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting β(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Furthermore, this chiral compound it is given as the R-enantiomer and acts as a full agonist. Cough was the most commonly reported adverse effect with use of indacaterol. Compared to salmeterol, it has 35% more agonist activity. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. [PMID: 22499359]
Mometasone furoate is a corticosteroid drug that can be used for the treatment of asthma, rhinitis, and certain skin conditions. It has a glucocorticoid receptor binding affinity 22 times stronger than dexamethasone and higher than many other corticosteroids as well. Mometasone furoate is formulated as a dry powder inhaler, nasal spray, and ointment for its different indications.
Mometasone is a synthetic corticosteroid with an affinity for glucocorticoid receptors 22 times higher than that of dexamethasone. Mometasone furoate also has a lower affinity to mineralocorticoid receptors than natural corticosteroids, making it more selective in its action. Mometasone furoate diffuses across cell membranes to activate pathways responsible for reducing inflammation.
| Trade Name | Indacaterol + Glycopyrronium + Mometasone Furoate |
| Generic | Indacaterol + Glycopyrronium + Mometasone Furoate |
| Type | |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | Bangladesh |
| Last Updated: | September 24, 2024 at 5:38 am |
Uses
It is indicated as a maintenance treatment of asthma, and to reduce asthma exacerbations, in adults not adequately controlled with a maintenance combination of a long-acting ß2-agonist and an inhaled corticosteroid.Indacaterol + Glycopyrronium + Mometasone Furoate is also used to associated treatment for these conditions: Airway Obstruction, Chronic Obstructive Pulmonary Disease (COPD), Increased upper airway secretion, Peptic Ulcer, Primary Axillary Hyperhidrosis, Sialorrhea (Excessive Drooling), Cardiac vagal inhibitory reflexes, Cardiac vagal inhibitory reflexes caused by General Surgery, Cardiac vagal inhibitory reflexes caused by Medication, Gastric secretions, Peripheral muscarinic effectsAsthma, Chronic Obstructive Pulmonary Disease (COPD), MaintenanceAllergic Rhinitis (AR), Asthma, Dermatitis, Dermatitis, Eczematous caused by superficial Fungal skin infection, Moderate to Severe Plaque Psoriasis, Polyps, Nasal, Pruritus, Psoriasis, Psoriasis, Moderate to Severe, Seasonal Allergies, Skin Diseases, Eczematous, Skin Infections
How Indacaterol + Glycopyrronium + Mometasone Furoate works
Glycopyrronium is a muscarinic antagonist with the highest affinity for M1 receptors, followed by M3, M2/M4, and M5.
Muscarinic receptors M1 to M4 are found in the lung, although M3 is predominantly responsible for bronchoconstriction and airway secretions. Secretions from salivary and sweat glands, as well as gastric acid secretions, are also predominantly mediated by the M3 receptor. Salivary and gastric acid secretions are also partially mediated by the M1 receptor. Antagonism of these receptors decreases the volume of their respective secretions, and in the case of the gastrointestinal system, reduces the acidity of the stomach.
In the cardiovascular system, muscarinic receptors M1 to M5 are all present, however the function of M5 has not been described in literature. Under normal circumstances, stimulation of the vagal nerve lowers the heart rate, potentially leading to intraoperative bradycardia. Studies in mice suggest that this stimulation is predominantly mediated by the M3 receptor, and mutant knockout mice are not susceptible to these effects.
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.
In asthma, mometasone is believed to inhibit mast cells, eosinophils, basophils, and lymphocytes. There is also evidence of inhibition of histamine, leukotrienes, and cytokines.
Corticosteroids diffuse across cell membranes into the cytosol of cells where they bind to glucocorticoid receptors to produce their activity. Mometasone furoate has a particularly high receptor affinity compare to other corticosteroids, 22 times higher than that of dexamethasone. Mometasone furoate binding to a glucocorticoid receptor causes conformational changes in the receptor, separation from chaperones, and the receptor moves to the nucleus. Once at the nucleus, receptors dimerize and bind to a DNA sequence known as the glucocorticoid response element which either increases expression of anti-inflammatory molecules or inhibits expression of pro-inflammatory molecules (such as interleukins 4 and 5). Mometasone furoate also reduces inflammation by blocking transcription factors such as activator-protein-1 and nuclear factor kappa B (NF-kappaB).
Dosage
Indacaterol + Glycopyrronium + Mometasone Furoate dosage
For oral inhalation only, to be used with inhalation device One inhalation capsule to be inhaled once daily Do not take more than one inhalation capsule in a daySide Effects
The most common adverse reactions over 52 weeks are nasopharyngitis, upper respiratory tract infection and headache.Toxicity
Patients presenting with an overdose typically present with flushing, hyperthermia, tachycardia, ileus, urinary retention, loss of ocular accommodation, light sensitivity, mydriasis, nausea, vomiting, dizziness, light headedness, and obstipation. Patients should be treated with symptomatic and supportive therapy, which may include the use of catheters for urinary retention, cardiovascular support, airway maintenance, ventilation, or neostigmine.
The oral LD50 in mice is 570 mg/kg, and in rats is 709 mg/kg. The intraperitoneal LD50 in mice is 90 mg/kg, and in rats is 196 mg/kg.
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.
Overdose with a mometasone furoate inhaler may occur with chronic overuse. Symptoms of chronic overuse may present as hypercorticism and adrenal suppression, and patients may not require any more treatment than monitoring.
In animal studies of pregnancy, some fetal toxic effects were seen at or above the maximum recommended human dose, though rodents are more sensitive to these effects than humans. The benefits and risks of use should be considered in pregnant patients
It is unknown if mometasone furoate is excreted in breast milk but other corticosteroids are and therefore caution should be exercised when administering to nursing mothers.
Safety and effectiveness in pediatric populations has been established through clinical trials, though there may be a reduction in expected growth of about 1cm per year depending on the dose and duration of treatment. Pediatric patients should be titrated to the lowest effective dose for mometasone furoate inhalers.
A trial of geriatric patients showed no difference in safety or efficacy compared to younger patients, however patients of an even greater age may still be more sensitive to mometasone furoate.
The use of a mometasone furoate inhaler in moderate or severe hepatic impairment rarely leads to detectable plasma concentrations though caution may be prudent with increasing degrees of severity.
The effects of mometasone furoate in renal impairment, and across gender and race have not been studied.
Precaution
This should not be used to treat acute asthma symptoms including acute episodes of bronchospasm. If any allergic reactions occur, like angioedema, urticaria, this combination should be discontinued immediately, and alternative therapy is instructed. This combination may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, or symptoms. If such effects occur, treatment may need to be discontinued. Inhalation of high doses of ß2-adrenergic agonists and corticosteroids may increase in plasma glucose. Upon initiation of treatment with this combination, plasma glucose should be monitored more closely in diabetic patients. In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse their mouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribed dose. This must not be swallowed. Only to be used with inhalation device. Removecapsule from the blister pack only immediately before use it in the inhalation device.Interaction
This combination, like other medicinal products containing LABA, should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants or medicinal products known to prolong the QT interval. Concomitant treatment with methylxanthine derivatives, steroids or non-potassium-sparing diuretics may potentiate the possible hypokalemic effect of LABA. This combination should not be given together with ß2-adrenergic blockers.Volume of Distribution
The mean volume of distribution in patients aged 1-14 years old is 1.3-1.8 L/kg, with a range of 0.7-3.9 L/kg. The volume of distribution in adults aged 60-75 years is 0.42 ± 0.22 L/kg.
After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution.
Steady state volume of distribution of 152L.
Elimination Route
In adults, a 66 mg topical dose of glycopyrronium reaches a Cmax of 0.08 ± 0.04 ng/mL, with a Tmax of 1 hour, and an AUC0-24 of 0.88 ± 0.57 h*ng/mL.
Inhaled glycopyrronium is approximately 40% bioavailable. A 25 µg inhaled solution reaches a Cmax of 34.5 pg/mL, with a Tmax of 0-inf of 255 h*pg/mL.
An 8 µg/kg intramuscular dose reaches a Cmax of 3.47 ± 1.48 µg/L, with a Tmax of 27.48 ± 6.12 minutes, and an AUC of 6.64 ± 2.33 h*g/L.
Oral glycopyrronium has highly variable pharmacokinetics, reaching a mean Cmax of 0.318 ng/mL, a Tmax of 3.1 hours, and an AUC0-24 of 1.74 h*ng/mL.
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%.
["\"Official drug label\" href=\"#label-reference","Label<\/a> but studies of repeat doses of inhaled corticosteroids suggest a bioavailability of 11%. The 0.1% ointment may have a bioavailability of 0.7%.<\/p>\n"]Half Life
The half life after inhalation is approximately 33-53 hours. The mean half life of a 6 µg/kg intravenous dose is 0.83 ± 0.27 hours. The mean half life of oral glycopyrronium is 3.0 hours.
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.
The terminal half life of an inhaled dose is approximately 5 hours though it has been reported as 5.8 hours by other sources.
Clearance
A 6 µg/kg intravenous dose has a clearance of 0.54 ± 0.14 L/kg/h. An oral solution has a clearance of 5.28-38.95 L/h/kg in healthy adults and 8.07-25.65 L/h/kg in patients with cerebral palsy.
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.
The clearance rate of mometasone furoate is not readily available, though it may be close to 90L/h.
Elimination Route
85% of an intravenous dose was recovered in the urine, with 12 >80% of the recovered dose is the unchanged parent drug. The remainder is recovered as the inactive M9 metabolite.
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).
For an inhaled dose, approximately 74% is excreted in the feces and 8% is excreted in the urine.
Pregnancy & Breastfeeding use
Pregnant Women: There are insufficient data on the use of indacaterol, glycopyrronium and mometasone furoate in pregnant women to inform a drug-associated risk. Indacaterol and glycopyrronium were not teratogenic in rats and rabbits following subcutaneous or inhalation administration respectively. In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoate caused increased fetal malformations and decreased fetal survival and growth. This should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.Breast-feeding: There is no information available on the presence of indacaterol, glycopyrronium or mometasone in human milk, on the effects on a breastfed child, or on the effects on milk production. Other inhaled corticosteroids, similar to mometasone furoate, are transferred into human milk. Indacaterol, glycopyrronium and mometasone furoate have been detected in the milk of lactating rats. Glycopyrronium reached up to 10-fold higher concentrations in the milk of lactating rats than in the blood of the dam after intravenous administration.Contraindication
It is contraindicated in patients with hypersensitivity to any of the active substances or excipients.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
High doses of Glycopyrronium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 150 micrograms Glycopyrronium in healthy volunteers.
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
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.Innovators Monograph
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