Ultivent-M Dry Powder Inhalation Capsule (DPI)

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.

This is an inhalation powder drug product for delivery of a combination of Indacaterol Acetate (an ultra-LABA), Glycopyrronium Bromide (an ultra-LAMA), and Mometasone Furoate (an ICS) to patients by oral inhalation.

Indacaterol: It is an ultra-LABA. When inhaled, Indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonist at the human ß2-adrenergic receptor. In isolated human bronchus, Indacaterol has a rapid onset of action and a long duration of action.

Glycopyrronium: It is an ultra-LAMA, which works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, thereby dilating the airways.

Mometasone Furoate: Mometasone Furoate is a synthetic corticosteroid with high afnity for glucocorticoid receptors and local anti-infammatory properties. In vitro, Mometasone Furoate inhibits the release of leukotrienes from leukocytes of allergic patients.

Indacaterol: Indacaterol is a long-acting beta 2-adrenergic agonist for once-daily administration. The pharmacological effects of beta 2 -adrenoceptor agonists, 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 AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol is a weak partial agonist at beta 1 -receptors with a potency more than 24-fold greater at beta 2 -receptors compared to beta 1-receptors and is a full agonist at beta 3 -receptors with a potency 20-fold greater at beta 2-receptors compared to beta 3-receptors. When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a nearly full agonist at the human beta 2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action. Although beta 2-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1-receptors are the predominant receptors in the human heart, there are also beta 2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors. The precise function of beta 2-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective beta 2-adrenergic agonists may have cardiac effects.

Glycopyrronium: Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (anti-cholinergic). Glycopyrronium works by blocking the broncho-constrictor action of acetylcholine on airway smooth muscle cells thereby dilating the airways. Of the five known muscarinic receptor subtypes (M1-5), only subtypes M1-3 have a defined physiological function in the human lung. Glycopyrronium is a high affinity muscarinic receptor antagonist of these three receptor subtypes. It demonstrated 4- to 5-fold selectivity for the human M3 and M1 receptors over the human M2 receptor in competition binding studies. It has a rapid onset of action, as evidenced by observed receptor association/dissociation kinetic parameters and by the onset of action after inhalation in clinical studies. The long duration of action can be partly attributed to sustained drug concentrations in the lungs as reflected by the prolonged terminal elimination half-life of glycopyrronium after inhalation via the inhaler in contrast to the half-life after intravenous administration.

Mometasone furoate: Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory properties. Studies in asthmatic patients have demonstrated that inhaled mometasone furoate provides a favorable ratio of pulmonary to systemic activity. It is likely that much of the mechanism for the effects of mometasone furoate lies in its ability to inhibit the release of mediators of the inflammatory cascade. In vitro, mometasone furoate inhibits the release of leukotrienes (LT) from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of LT production and an extremely potent inhibitor of the production of the Th2 cytokines, IL-4 and IL-5, from human CD4+ T-cells.

• 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 day

• Ultivent-M, 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.
• Ultivent-M should not be given together with ß2-adrenergic blockers.

It is contraindicated in patients with hypersensitivity to any of the active substances or excipients.

The most common adverse reactions over 52 weeks are nasopharyngitis, upper respiratory tract infection and headache.

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.

• This should not be used to treat acute asthma symptoms including acute episodes of bronchospasm.
• If any allergic reactions occur, like angioedema, urticaria, Ultivent-M should be discontinued immediately, and alternative therapy is instructed.
• Ultivent-M 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 Ultivent-M, 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. Remove
  capsule from the blister pack only immediately before use it in the inhalation device.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.