SEEBRI NEOHALER

SEEBRI®NEOHALER® (glycopyrrolate) inhalation powder

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SEEBRI®NEOHALER®

SEEBRI NEOHALER consists of SEEBRI capsules and a NEOHALER device. Each SEEBRI capsule contains a dry powder formulation of glycopyrrolate packaged in orange transparent hypromellose (HPMC) capsules for oral inhalation with the NEOHALER device only.

Each orange transparent HPMC capsule contains 15.6 mcg of glycopyrrolate blended with approximately 25 mg of lactose monohydrate (which contains trace levels of milk protein) and 0.04 mg of magnesium stearate.

Glycopyrrolate, the active component of SEEBRI NEOHALER, 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 an inhalation device used to inhale the dry powder within the SEEBRI 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 device delivered 13.1 mcg for the 15.6 mcg dose strength (equivalent to 12.5 mcg of glycopyrronium) from the mouthpiece. This in vitro testing revealed that the NEOHALER device had a specific resistance of 0.07 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

SEEBRI NEOHALER is an anticholinergic indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

Dosage and administration

For oral inhalation only. Do not swallow SEEBRI capsules, as the intended effects on the lungs will not be obtained. SEEBRI capsules should only be used with the NEOHALER device.

The recommended dosage is one capsule of SEEBRI (15.6 mcg glycopyrrolate) inhalation powder twice daily by oral inhalation using the NEOHALER device. SEEBRI NEOHALER should be administered at the same time of the day, (1 capsule in the morning and 1 capsule in the evening), every day. More frequent administration or a greater number of inhalations (more than 1 capsule twice-daily) of SEEBRI NEOHALER is not recommended.

Mechanism of Action 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.

Pharmacodynamics

Cardiac Electrophysiology: The effect of SEEBRI NEOHALER on the QTc interval was evaluated in a Phase 1 randomized placebo and positive controlled double-blind, single-dose, crossover thorough QTc study in 73 healthy subjects. At the dose 16-fold the therapeutic daily dose, SEEBRI NEOHALER did not prolong QTc to any clinically relevant extent.

Pharmacokinetics

Absorption: Following oral inhalation using the NEOHALER inhaler, glycopyrrolate was rapidly absorbed and reached peak plasma levels at 5 minutes post dose.

The absolute bioavailability of glycopyrrolate inhaled via SEEBRI NEOHALER was estimated to be about 40%. About 90% of systemic exposure following inhalation is due to lung absorption and 10% is due to gastrointestinal absorption.

Following repeated once-daily inhalation in patients with COPD, PK steady-state of glycopyrrolate was reached within 1 week of treatment. There was no indication that the glycopyrrolate pharmacokinetics changes over time.

Distribution: After intravenous administration, the steady-state volume of distribution of glycopyrrolate was 83 L and the volume of distribution in the terminal phase 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: 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 indicating 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 was much longer after inhalation (33 to 53 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration.

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Metabolism: In vitro metabolism studies show glycopyrrolate hydroxylation resulting in a variety of mono- and bis-hydroxylated 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

History of known hypersensitivity to glycopyrrolate or to any of the ingredients.

Warnings and precautions

  • Do not initiate in acutely deteriorating COPD or to treat acute symptoms.
  • If paradoxical bronchospasm occurs, discontinue SEEBRI NEOHALER immediately and institute alternative therapy.
  • Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a physician immediately if symptoms occur.
  • Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder neck obstruction and instruct patients to consult a physician immediately if symptoms occur.

Adverse reactions

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

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

Drug interactions

Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of SEEBRI NEOHALER with other anticholinergic-containing drugs.

Use in specific populations

Pregnancy: There are no adequate and well-controlled studies with SEEBRI NEOHALER in pregnant women. Women should be advised to contact their physician if they become pregnant while taking SEEBRI NEOHALER.

In animal reproduction studies, there were no evidence of fetal harm or structural abnormalities in Wistar rats or New Zealand White rabbits at inhaled doses approximately 1,400 and 530 times, respectively, the maximum recommended human dose (MRHD of 31.2 mcg) on an area under the curve (AUC) basis.

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

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

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

Of the total number of subjects in clinical studies of SEEBRI NEOHALER, 45% were aged 65 and older, while 10% were aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment: No dose adjustment is recommended for patients with mild and moderate renal impairment. Use SEEBRI NEOHALER in patients with severe renal impairment [estimated glomerular filtration rate (GFR) less than 30 mL/min/1.73 m2 ], including those with end-stage renal disease requiring dialysis, only if the expected benefit outweighs the potential risk since the systemic exposure to glycopyrrolate may be increased in this population.

Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment. The effects of hepatic impairment on the pharmacokinetics of glycopyrrolate have not been studied.

Overdosage

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.

Accidental Ingestion: Acute intoxication by inadvertent oral ingestion of SEEBRI NEOHALER capsules is unlikely due to the low oral bioavailability (about 5%).

Storage and Handling

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

  • SEEBRI capsules should be used with the NEOHALER device only. Do not use the NEOHALER device with any other capsules.
  • Store SEEBRI capsules in the blister protected from moisture. Remove the SEEBRI 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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