UTIBRON ® NEOHALER ®

UTIBRON ® NEOHALER ® (indacaterol and glycopyrrolate)

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UTIBRON ® NEOHALER ®

UTIBRON NEOHALER consists of a dry powder formulation for delivery of a combination of indacaterol and glycopyrrolate to patients by oral inhalation only with the NEOHALER device. The inhalation powder is packaged in hypromellose (HPMC) capsules with yellow transparent cap and uncolored transparent body.

Each capsule contains a dry powder blend of 27.5 mcg/15.6 mcg of indacaterol/glycopyrrolate with approximately 24.9 mg of lactose monohydrate (which contains trace levels of milk protein) and 0.03 mg of magnesium stearate.

One active component of UTIBRON NEOHALER is indacaterol maleate, a (R) enantiomer. Indacaterol maleate is a selective beta 2 -adrenergic agonist. Its chemical name is (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8­ hydroxy-1H-quinolin-2-one maleate.

Indacaterol maleate has a molecular weight of 508.56 g/mol, and its empirical formula is C24H28N2O3 • C4H4O4. Indacaterol maleate is a white to very slightly grayish or very slightly yellowish powder. Indacaterol maleate is slightly soluble in ethanol and very slightly soluble in water.

The other active component of UTIBRON NEOHALER is glycopyrrolate, which is chemically described as (3RS)-3­ [(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy]-1,1-dimethylpyrrolidinium bromide. This synthetic quaternary ammonium compound acts as a competitive antagonist at muscarinic acetylcholine receptors, also referred to as anticholinergic. Glycopyrrolate, C19H28BrNO3 , is a white powder that is freely soluble in water and sparingly soluble in absolute ethanol. It has a molecular mass of 398.33 g/mol.

The NEOHALER device is a plastic inhalation device used to inhale the dry powder within the UTIBRON capsule. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time.

Under standardized in vitro testing at a fixed flow rate of 90 L/min for 1.3 seconds, the NEOHALER inhaler delivered 20.8 mcg of indacaterol and 12.8 mcg glycopyrrolate for the 27.5 mcg/15.6 mcg dose strength (equivalent to 27.5 mcg/12.5 mcg of indacaterol/glycopyrronium) from the mouthpiece. This in vitro testing revealed that the NEOHALER device had a specific resistance of 0.059 cm H2O1/2/L/min. Peak inspiratory flow rates (PIFR) achievable through the NEOHALER device were evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95 L/min (range 52 to 133 L/min) for adult patients. Twenty-five of 26 patients (96%) in this study generated a PIFR through the device exceeding 60 L/min.

Indications

UTIBRON NEOHALER is a combination of indacaterol, a long-acting beta2­ adrenergic agonist (LABA), and glycopyrrolate, an anticholinergic, indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

Limitations of Use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma

Dosage and administration

  • For oral inhalation only. Do not swallow UTIBRON capsules. Use UTIBRON capsules only with the NEOHALER device.
  • Maintenance treatment of COPD: 27.5 mcg of indacaterol and 15.6 mcg glycopyrrolate inhalation powder (contents of one UTIBRON capsule) twice daily by oral inhalation.

Mechanism of Action

UTIBRON NEOHALER contains both indacaterol and glycopyrrolate. The mechanisms of action described below for the individual components apply to UTIBRON NEOHALER. These drugs represent 2 different classes of medications (a LABA and an anticholinergic) that have different and additive effects on clinical and physiological indices.

Indacaterol: Indacaterol is a LABA. When inhaled, indacaterol acts locally in the lung as a bronchodilator. 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. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the 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 these receptors is not known, but their presence raises the possibility that even highly selective beta 2 -adrenergic agonists may have cardiac effects.

The pharmacological effects of beta 2 -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 AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Glycopyrrolate: Glycopyrrolate is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine and acetylcholine -induced bronchoconstrictive effects was dosedependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect.

Pharmacokinetics

Absorption

Following inhalation of UTIBRON NEOHALER, the median time to reach peak plasma concentrations of indacaterol and glycopyrrolate was achieved rapidly at approximately 15 minutes and 5 minutes, respectively.

The steady-state systemic exposure (AUC0-12h,ss ; Cmax,ss ) to indacaterol and glycopyrrolate is similar after thetwice-daily inhalation of 2 (times 2) capsules of UTIBRON NEOHALER 27.5 mcg/15.6 mcg as compared to the twice-daily inhalation of the monotherapy products indacaterol 27.5 mcg (times 2) alone or glycopyrrolate 15.6 mcg (times 2) alone, respectively.

Indacaterol: Absolute bioavailability of indacaterol after an inhalation dose was on average 43% to 45%. Systemic exposure results from a composite of pulmonary and intestine absorption.

Indacaterol serum concentrations increased with repeated once daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, i.e., AUC over the 24-hour dosing interval on Day 14 or Day 15 compared to Day 1, was in the range of 2.9 to 3.8 for once daily inhaled doses between 75 mcg and 600 mcg.

Glycopyrrolate: Following repeated once daily inhalation in patients with COPD, pharmacokinetic steady-state of glycopyrrolate was reached within 1 week of treatment. There was no indication that the glycopyrrolate pharmacokinetics changes over time. With once daily doses of 124.8 mcg and 249.6 mcg, steady-state exposure to glycopyrrolate (AUC over the dosing interval) was about 1.4- to 1.7-fold higher than after the first dose.

Distribution

Indacaterol: After intravenous infusion,the volume of distribution (Vz) of indacaterol was 2361 to 2557 L, indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1% to 95.3% and 95.1% to 96.2%, respectively.

Glycopyrrolate: After intravenousadministration, the steady-state volume of distribution (Vss) of glycopyrrolate was 83 L and the volume of distribution in theterminal phase (Vz) was 376 L. The in vitro human plasma protein binding of glycopyrrolate was 38% to 41% at concentrations of 1 to 10 ng/mL.

Elimination

Indacaterol: In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 L/h and 1.20 L/h. When compared with the serum clearance of indacaterol of 18.8 L/h to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2% to 6% of systemic clearance) in the elimination of systemically available indacaterol.

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Glycopyrrolate: Renal elimination of parent drug accounts for about 60% to 70% of total clearance of systemically available glycopyrrolate whereas non-renal clearance processes account for about 30% to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.

Following inhalation of single and repeated once daily doses between 62.4 mcg and 249.6 mcg glycopyrrolate by healthy volunteers and patients with COPD, mean renal clearance of glycopyrrolate was in the range of 17.4 L/h and 24.4 L/h. Active tubular secretion contributes to the renal elimination of glycopyrrolate.

Glycopyrrolate plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life of glycopyrrolate was much longer after inhalation (33 to 53 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration.

Metabolism

Indacaterol: In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.

Glycopyrrolate: In vitro metabolism studies show glycopyrrolate hydroxylation resulting in a variety of mono- and bis­hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9). Further in vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrrolate and the hydrolysis to M9 is likely to be catalyzed by members from the cholinesterase family pre-systemically and/or via first pass metabolism from the swallowed dose fraction of orally inhaled glycopyrrolate. Glucuronide and/or sulfate conjugates of glycopyrrolate were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.

Contraindications

  • Use of a LABA, including UTIBRON NEOHALER, without an inhaled corticosteroid is contraindicated in patients with asthma.
  • History of known hypersensitivity to indacaterol, glycopyrrolate, or to any of the ingredients

Adverse reactions

Most common adverse reactions (incidence greater than or equal to 2% and higher than placebo) are nasopharyngitis and hypertension.

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch3T.

Drug interactions

  • Other adrenergic drugs may potentiate effect: Use with caution.
  • Xanthine derivatives, steroids, diuretics or non-potassium-sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution.
  • Monoamine Oxidase inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval may potentiate effect on cardiovascular system. Use with extreme caution.
  • Beta-blockers may decrease effectiveness: Use with caution and only when medically necessary.
  • Anticholinergics: may interact additively with concomitantly used anticholinergic medications. Avoid administration of UTIBRON NEOHALER with other anticholinergic-containing drugs.

Warnings and precautions

  • LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events
  • Do not initiate in acutely deteriorating COPD or to treat acute symptoms.
  • Do not use in combination with an additional medication containing LABA because of risk of overdose.
  • If paradoxical bronchospasm occurs, discontinue UTIBRON NEOHALER immediately and institute alternative therapy.
  • Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, sensitivity to sympathomimetic drugs, diabetes mellitus, and ketoacidosis.
  • Worsening of narrow-angle glaucoma or urinary retention may occur. Use with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction and instruct patients to contact their healthcare provider immediately if symptoms occur.
  • Be alert to hypokalemia and hyperglycemia.
Use in specific populations:

Pregnancy: There are no adequate and well-controlled studies with UTIBRON NEOHALER or its individual components, indacaterol and glycopyrrolate, in pregnant women. Women should be advised to contact their healthcare provider if they become pregnant while taking UTIBRON NEOHALER.

Lactation: There is no data on the presence of indacaterol or glycopyrrolate or their metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, in studies of lactating rats, indacaterol and glycopyrrolate were present in the milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UTIBRON NEOHALER and any potential adverse effects on the breastfed child from UTIBRON NEOHALER or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of UTIBRON NEOHALER in pediatric patients have not been established. UTIBRON NEOHALER is not indicated for use in pediatric patients.

Geriatric Use: Based on available data, no adjustment of UTIBRON NEOHALER dosage in geriatric patients is warranted. UTIBRON NEOHALER can be used at the recommended dosage in elderly patients 75 years of age and older.

Renal Impairment: Based on the pharmacokinetic characteristics of its monotherapy components, UTIBRON NEOHALER can be used at the recommended dose in patients with mild to moderate renal impairment. In patients with severe renal impairment (e stimated GFR less than 30 mL/min/1.73 m2) or end-stage renal disease requiring dialysis, use UTIBRON NEOHALER only if the expected benefit outweighs the potential risk since the systemic exposure to glycopyrrolate may be increased in this population.

Hepatic Impairment: Based on the pharmacokinetic characteristics of its monotherapy components, UTIBRON NEOHALER can be used at the recommended dose in patients with mild and moderate hepatic impairment. Studies in subjects with severe hepatic impairment have not been performed

Overdosage

In COPD patients, doses higher than the recommended dosage of UTIBRON NEOHALER were associated with an increase in ventricular ectopies after 14 days of dosing with 300/124.8 mcg and 600/124.8 mcg UTIBRON NEOHALER. In a total of four patients, non-sustained ventricular tachycardia was recorded, with the longest episode recorded being 9 beats (4 seconds).

Indacaterol: The potential 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 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, vomiting, drowsiness, 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.

Glycopyrrolate: An overdosage of glycopyrrolate may lead to anticholinergic signs and symptoms, such as nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure (causing pain, vision disturbances, or reddening of the eye), obstipation or difficulties in voiding.

Storage and Handling

Store in a dry place at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].

  • UTIBRON capsules should be used with the NEOHALER device only. Do not use the NEOHALER device with any other capsules.
  • Store UTIBRON capsules in the blister protected from light and moisture. Remove the UTIBRON capsules from the blister immediately before use.
  • Always use the new NEOHALER inhaler provided with each new prescription.

Keep out of the reach of children.

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