LONHALA MAGNAIR (Page 2 of 4)

7. DRUG INTERACTIONS

7.1. Sympathomimetics and Steroids

In clinical studies, concurrent administration of glycopyrrolate and other drugs commonly used in the treatment of COPD including sympathomimetics (long and short-acting beta2 agonists), anticholinergics (short-acting anti-muscarinic antagonists) and oral and inhaled steroids showed no increases in adverse drug reactions.

7.2. Anticholinergics

There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid unnecessary co-administration of LONHALA MAGNAIR with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].

8. USE IN SPECIFIC POPULATIONS

8.1. Pregnancy

Risk Summary

There are no adequate and well-controlled studies in pregnant women. LONHALA MAGNAIR should only be used during pregnancy if the expected benefit to the patient outweighs the potential risk to the fetus. Women should be advised to contact their physician if they become pregnant while taking LONHALA MAGNAIR. In animal reproduction studies, there were no teratogenic effects in Wistar rats and New Zealand White rabbits at inhaled doses approximating 1521 and 580 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) based on an AUC comparison [see Data ].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Labor or Delivery

The potential effect of LONHALA MAGNAIR on labor and delivery is unknown. LONHALA MAGNAIR should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.

Data

Animal Data

Developmental studies in Wistar rats and New Zealand White rabbits in which glycopyrrolate was administered by inhalation during the period of organogenesis did not result in evidence of teratogenicity at exposures approximately 1521 and 580 times, respectively, the MRHDID of LONHALA MAGNAIR based on a comparison of plasma AUC levels (maternal doses up to 3.8 mg/kg/day in rats and 4.4 mg/kg/day in rabbits).

Glycopyrrolate had no effects on peri-natal and post-natal development in rats following subcutaneous exposure of approximately 1137 times the MRHDID of LONHALA MAGNAIR based on an AUC comparison (at a maternal dose of up to 1.885 mg/kg/day).

8.2. Lactation

Risk Summary

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 [see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LONHALA MAGNAIR and any potential adverse effects on the breastfed infant from LONHALA MAGNAIR or from the underlying maternal condition.

Data

Glycopyrrolate (and its metabolites) was detected in the milk of lactating rats following a single intravenous injection of 4 mg/kg of radiolabeled glycopyrrolate.

8.4. Pediatric Use

LONHALA MAGNAIR is not indicated for use in children. The safety and efficacy of LONHALA MAGNAIR in pediatric patients have not been established.

8.5. Geriatric Use

Based on available data, no adjustment of the dosage of LONHALA MAGNAIR in geriatric patients is warranted. LONHALA MAGNAIR 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 LONHALA MAGNAIR, 41% were aged 65 and older, while 8% 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.

8.6. Renal Impairment

No dose adjustment is required for patients with mild and moderate renal impairment. The effects of renal impairment on the pharmacokinetics of glycopyrrolate have not been studied [see Clinical Pharmacology (12.3) ].

8.7. Hepatic Impairment

No dose adjustment is required for patients with hepatic impairment. The effects of hepatic impairment on the pharmacokinetics of glycopyrrolate have not been studied [see Clinical Pharmacology (12.3) ].

10. OVERDOSAGE

An overdose 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.

In COPD patients, orally inhaled administration of LONHALA MAGNAIR at a total daily dose of 200 mcg for 28 consecutive days (maximum of 1 mg) was well tolerated. Pharmacokinetic results from several studies conducted in COPD patients showed that a single, well tolerated dose of 1000 mcg had a Cmax of 1534 pg/mL and AUC0-inf of 5271 pg*hr/mL. These values are approximately 44 fold and 21 fold higher, respectively, than the estimated daily Cmax of 34.5 pg/mL and AUC0-inf of 255 pg*hr/mL for a 25 mcg BID dose regimen at steady-state.

11. DESCRIPTION

LONHALA MAGNAIR consists of LONHALA vials and a MAGNAIR nebulization system. LONHALA (glycopyrrolate) Inhalation Solution is a sterile, clear, colorless, aqueous solution for oral inhalation.

Glycopyrrolate USP, the active component of LONHALA Inhalation Solution, is chemically described as (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-penylacetyl)oxy]-1,1-dimethlypyrrolidinium bromide. Glycopyrrolate is a synthetic quaternary ammonium compound that acts as a competitive antagonist at muscarinic acetylcholine receptors, also referred to as an anticholinergic. Glycopyrrolate, C19 H28 BrNO3, is a white, odorless, crystalline powder that is soluble in water and in alcohol. It has a molecular mass of 398.33. The structural formula is:

Structural Formula
(click image for full-size original)

The inactive ingredients in LONHALA are: citric acid monohydrate, sodium chloride, sodium hydroxide and water for injection.

LONHALA Inhalation Solution is supplied in low-density polyethylene (LDPE) unit dose vials, each containing 1.0 mL of the solution. Each unit-dose vial contains 25 mcg of glycopyrrolate in a sterile, isotonic saline solution, pH-adjusted to 4.0 with citric acid and sodium hydroxide.

Like all other nebulized treatments, the amount delivered to the lungs will depend upon patient factors. Under standardized in vitro testing per USP<1601> adult breathing pattern (500 mL tidal volume, 15 breaths per minute, and inhalation: exhalation ratio of 1:1), the mean delivered dose from the mouthpiece was approximately 14.2 mcg of glycopyrrolate (equivalent to 11.4 mcg glycopyrronium and 56.8% label claim). The mass median aerodynamic diameter (MMAD) of the nebulized aerosol particles/droplets is 3.71 μm 95% CI (2.92 — 4.49 μm) as determined using the Next Generation Impactor (NGI) method. The mean nebulization time was approximately 2 to 3 minutes.

12. CLINICAL PHARMACOLOGY

12.1. 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 dose-dependent 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.

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