ARCAPTA® NEOHALER®

ARCAPTA® NEOHALER® (indacaterol inhalation powder)

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ARCAPTA® NEOHALER®

ARCAPTA NEOHALER consists of a dry powder formulation of indacaterol maleate for oral inhalation only with the NEOHALER inhaler. The inhalation powder is packaged in clear gelatin capsules.

Each clear, hard gelatin capsule contains a dry powder blend of 75 mcg of indacaterol (equivalent to 97 mcg of indacaterol maleate) with approximately 25 mg of lactose monohydrate (which contains trace levels of milk protein) as the carrier.

The active component of ARCAPTA NEOHALER is indacaterol maleate, a (R) enantiomer. Indacaterol maleate is a selective beta2-adrenergic agonist. Its chemical name is (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8­hydroxy-1H-quinolin-2-one maleate.

Indacaterol maleate has a molecular weight of 508.56, and its empirical formula is C24H28N2O3 • C4 H4O4. Indacaterol maleate is a white to very slightly grayish or very slightly yellowish powder. Indacaterol maleate is freely soluble in Nmethylpyrrolidone and dimethylformamide, slightly soluble in methanol, ethanol, propylene glycol and polyethylene glycol 400, very slightly soluble in water, isopropyl alcohol and practically insoluble in 0.9% sodium chloride in water, ethyl acetate and n-octanol

The NEOHALER inhaler is a plastic device used for inhaling ARCAPTA. 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 60 L/min for 2 seconds, the NEOHALER inhaler delivered 57 mcg for the 75 mcg dose strength (equivalent to 73.9 mcg of indacaterol maleate) from the mouthpiece. Peak inspiratory flow rates (PIFR) achievable through the NEOHALER inhaler were evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95 L/min (range 52-133 L/min) for adult patients. Approximately ninety-five percent of the population studied generated a PIFR through the device exceeding 60 L/min.

Indications

ARCAPTA NEOHALER is a long-acting beta2-adrenergic agonist indicated for: The long term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important limitations:

  • ARCAPTA NEOHALER is NOT indicated to treat acute deteriorations of chronic obstructive pulmonary disease.
  • ARCAPTA NEOHALER is NOT indicated for asthma.

Mechanism of Action

Indacaterol is a long-acting beta2-adrenergic agonist.

When inhaled, indacaterol acts locally in the lung as a bronchodilator. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-adrenergic receptors in the human heart comprising 10%-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 beta2- adrenergic agonists may have cardiac effects.

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.

Pharmacokinetics

Absorption: The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose (150 mcg to 600 mcg) in a dose proportional manner, and was about dose-proportional in the dose range of 75 mcg to 150 mcg. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%. Systemic exposure results from a composite of pulmonary and intestinal 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.

Distribution: After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution. The human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.

Metabolism: After oral administration of radiolabeled indacaterol in the human ADME (absorption, distribution, metabolism, excretion) study unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.

In vitro investigations indicated that UGT1A1 was 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 indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.

In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions with medications (by inhibition or induction of cytochrome P450 enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in clinical practice. In vitro investigation furthermore indicated that, in vivo, indacaterol is unlikely to significantly inhibit transporter proteins such as P-gp, MRP2, BCRP, the cationic substrate transporters hOCT1 and hOCT2, and the human multidrug and toxin extrusion transporters hMATE1 and hMATE2K, and that indacaterol has negligible potential to induce P-gp or MRP2.

Elimination: 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 and 1.2 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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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). Mass balance was complete with ≥90% of the dose recovered in the excreta.

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.

Dosage and administration

For oral inhalation only. DO NOT swallow ARCAPTA capsule. ARCAPTA capsules should always be used with the NEOHALER inhaler only. 75 mcg inhaled every day (once-daily).

ARCAPTA capsules must always be stored in the blister, and only removed IMMEDIATELY BEFORE USE.

No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renallyimpaired patients. No data are available for subjects with severe hepatic impairment.

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.
  • MAO 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

Contraindications

Use of a LABA, including ARCAPTA NEOHALER, without an inhaled corticosteroid is contraindicated in patients with asthma. ARCAPTA NEOHALER is not indicated for the treatment of asthma.

ARCAPTA NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol or to any of the ingredients.

Adverse reactions

Most common adverse reactions (>2% and more common than placebo) are cough, oropharyngeal pain, nasopharyngitis, headache and nausea.

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 patients.
  • Do not use for relief of acute symptoms. Concomitant short-acting beta2-agonists can be used as needed for acute relief.
  • Do not exceed the recommended dose. Excessive use or use in conjunction with other medications containing LABA can result in clinically significant cardiovascular effects and may be fatal.
  • Immediate hypersensitivity reactions may occur. Discontinue immediately.
  • Life-threatening paradoxical bronchospasm can occur. Discontinue immediately.
  • Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis or sensitivity to sympathomimetic drugs.
Overdosage

The expected signs and symptoms associated with overdosage of ARCAPTA NEOHALER are those of excessive beta2-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 ARCAPTA NEOHALER.

Treatment of overdosage consists of discontinuation of ARCAPTA NEOHALER together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of ARCAPTA NEOHALER. Cardiac monitoring is recommended in cases of overdosage.

Use in specific populations

Pregnancy: Teratogenic Effects: Pregnancy Category C.

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

Indacaterol was not teratogenic following subcutaneous administration to rats and rabbits at doses up to 1 mg/kg, 2approximately 130 and 260 times, respectively, the 75 mcg dose on a mg/mPbasis.

Labor and Delivery: There are no adequate and well-controlled human studies that have investigated effects of ARCAPTA NEOHALER on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of ARCAPTA NEOHALER during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers: It is not known that the active component of ARCAPTA NEOHALER, 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 ARCAPTA NEOHALER is administered to nursing women.

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

Geriatric Use: Based on available data, no adjustment of ARCAPTA NEOHALER dosage in geriatric patients is warranted. Of the total number of patients who received ARCAPTA NEOHALER at the recommended dose of 75 mcg once daily in the clinical studies from the pooled 3-month database, 239 were <65 years, 153 were 65-74 years and 57 were ≥75 years of age.

Storage and Handling

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

75 mcg: Protect capsule from light and moisture.

  • ARCAPTA capsules should be used with the NEOHALER inhaler only. The NEOHALER inhaler should not be used with any other capsules.
  • Capsules should always be stored in the blister and only removed 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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