Ultivent-M Inhalation Capsule 150 mcg+50 mcg+160 mcg

Uses

Ultivent-M Inhalation Capsule 150 mcg+50 mcg+160 mcg 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 Ultivent-M Inhalation Capsule 150 mcg+50 mcg+160 mcg 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

Ultivent-M Inhalation Capsule 150 mcg+50 mcg+160 mcg dosage

Side Effects

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

Interaction

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 C_max of 0.08 ± 0.04 ng/mL, with a T_max of 1 hour, and an AUC_0-24 of 0.88 ± 0.57 h*ng/mL.

Inhaled glycopyrronium is approximately 40% bioavailable. A 25 µg inhaled solution reaches a C_max of 34.5 pg/mL, with a T_max of 0-inf of 255 h*pg/mL.

An 8 µg/kg intramuscular dose reaches a C_max of 3.47 ± 1.48 µg/L, with a T_max 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 C_max of 0.318 ng/mL, a T_max of 3.1 hours, and an AUC_0-24 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%.

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

Contraindication

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

Innovators Monograph

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