SEEBRI NEOHALER (GLYCOPYRROLATE) capsule

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 [see Overdosage (10)].

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.

SEEBRI NEOHALER should not be initiated in patients during acutely deteriorating or potentially life-threatening episodes of COPD. SEEBRI NEOHALER has not been studied in subjects with acutely deteriorating COPD. The initiation of SEEBRI NEOHALER in this setting is not appropriate.

SEEBRI NEOHALER should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. SEEBRI NEOHALER has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta₂-agonist.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If SEEBRI NEOHALER no longer controls symptoms of bronchoconstriction; the patient's inhaled, short-acting beta₂-agonist becomes less effective; or the patient needs more inhalation of a short-acting beta₂-agonist than usual, these may be markers of deterioration of disease. In this setting, a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of SEEBRI NEOHALER beyond the recommended dose is not appropriate in this situation.

As with other inhaled medicines, SEEBRI NEOHALER can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs following dosing with SEEBRI NEOHALER, it should be treated immediately with an inhaled, short-acting bronchodilator; SEEBRI NEOHALER should be discontinued immediately, and alternative therapy instituted.

Immediate hypersensitivity reactions have been reported after administration of SEEBRI NEOHALER. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips, and face), urticaria, or skin rash, SEEBRI NEOHALER should be discontinued immediately and alternative therapy instituted. SEEBRI NEOHALER should be used with caution in patients with severe hypersensitivity to milk proteins.

SEEBRI NEOHALER should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

SEEBRI NEOHALER should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

The SEEBRI NEOHALER safety database included 3415 subjects with COPD in four 12-week lung function trials and one 52-week long-term safety study. A total of 1202 subjects received treatment with SEEBRI NEOHALER 15.6 mcg twice daily. The safety data described below are based on the four 12-week trials and the one 52-week trial.

12-Week Trials

The incidence of adverse reactions associated with SEEBRI NEOHALER in Table 1 is based on four 12-week, placebo-controlled trials in 2908 subjects with COPD. In the total population, 61.2% of patients had moderate COPD and 37.8% had severe COPD. In these trials, 951 subjects received SEEBRI NEOHALER 15.6 mcg twice daily, 511 subjects received indacaterol 27.5 mcg twice daily, 508 subjects received a fixed-dose combination of indacaterol/glycopyrrolate 27.5 mcg/15.6 mcg twice daily, and 938 subjects received placebo. Overall, 62% were males, 90% were Caucasian, and the mean age was 63 years (ranging from 41 to 89 years). In this population, 53% were identified as current smokers with an average smoking history of 48 pack-years.

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

The proportion of subjects who discontinued treatment due to adverse reactions was 2.4% for the SEEBRI NEOHALER-treated patients and 3.8% for placebo-treated patients.

Other adverse reactions occurring more frequently with SEEBRI NEOHALER than with placebo, but with an incidence of less than 1% include rash, pruritus, gastroenteritis, hypersensitivity, atrial fibrillation, insomnia, pain in extremity, dysuria, vomiting, productive cough, and diabetes mellitus/hyperglycemia.

52-Week Trial

In a long-term safety trial, 507 subjects were treated for up to 52 weeks with glycopyrrolate 15.6 mcg twice daily or indacaterol 75 mcg once daily. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled efficacy trials described above. The adverse reactions reported in the long-term safety trial were consistent with those observed in the placebo-controlled trials of 12 weeks. Additional adverse reactions that occurred with a frequency greater than or equal to 2% in the group receiving glycopyrrolate 15.6 mcg twice daily that exceeded the frequency of indacaterol 75 mcg once daily in this trial were: diarrhea, nausea, upper abdominal pain, fatigue, bronchitis, pneumonia, rhinitis, back pain, arthralgia, dyspnea, and wheezing.

The following additional adverse reactions have been identified during worldwide post-approval use of glycopyrrolate, the active ingredient in SEEBRI NEOHALER, at higher than the recommended dose. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are: angioedema, paradoxical bronchospasm and dysphonia.

In clinical studies, concurrent administration of short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators (including indacaterol), methylxanthines, oral and inhaled steroids with SEEBRI NEOHALER showed no increases in adverse drug reactions.

There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of SEEBRI NEOHALER 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)].

Risk Summary

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 (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Labor or Delivery

The potential effect of SEEBRI NEOHALER on labor and delivery is unknown. SEEBRI NEOHALER 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

In embryo-fetal development studies, pregnant Wistar rats received daily inhalation doses of glycopyrrolate, during the period of organogenesis from gestation days 7 to 17, at exposures up to 1,400 times the MRHD (on an AUC basis with maternal inhaled doses up to 3.83 mg/kg) and pregnant New Zealand White rabbits received daily inhalation doses of glycopyrrolate, during the period of organogenesis from gestation days 7 to 19, at exposures up to 530 times the MRHD on an AUC basis with maternal inhaled doses up to 4.4 mg/kg). Glycopyrrolate produced no evidence of teratogenicity in Wistar rats or New Zealand White rabbits at exposures up to approximately 1,400 and 530 times, respectively the MRHD.

In a pre- and postnatal development study in pregnant Wistar rats, glycopyrrolate was administered subcutaneously daily throughout the periods of organogenesis and lactation from gestation day 6 through lactation day 23 at exposures up to 1,100 times the MRHD (on an AUC basis with maternal subcutaneous doses up to 1.88 mg/kg/day). Glycopyrrolate had no effects on physical, neurological, or reproductive development in rats following exposures up to approximately 1,100 times the MRHD.

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 SEEBRI NEOHALER and any potential adverse effects on the breastfed child from SEEBRI NEOHALER or from the underlying maternal condition.

Data

Animal Data

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

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

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.

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/1.73m²], 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 [see Clinical Pharmacology (12.3)].

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

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.

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.

Linear pharmacokinetics of glycopyrrolate was observed following inhalation of daily doses of 31.2 mcg to 249.6 mcg.

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.

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.

Drug Interaction Studies

In vitro inhibition studies demonstrated that glycopyrrolate has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrrolate for any of the cytochrome P450 isoenzymes tested as well as for UGT1A1 and the transporters MDR1 and MRP2.

In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport which is thought to contribute to the renal excretion of glycopyrrolate, increased total systemic exposure (AUC) to glycopyrrolate by 22% and decreased renal clearance by 23%.

Specific Populations

Population pharmacokinetic analysis showed no evidence of a clinically relevant effect of age (40 to 85 years) or body weight (45 to 120 kg) on systemic exposure to glycopyrrolate. In addition, there was no evidence of a clinically significant ethnic/race effect (across Caucasian, Chinese, Hispanic/Latino, Japanese subjects). Gender, smoking status, and baseline FEV₁ have no apparent effect on maximal or average glycopyrrolate systemic exposure.

Patients with Renal Impairment: Renal impairment has an impact on the systemic exposure to glycopyrrolate. A moderate mean increase in total systemic exposure (AUC_last) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment [estimated GFR greater than or equal to 30 mL/min/1.73m²] and up to 2.2-fold in subjects with severe renal impairment and end stage renal disease [estimated GFR less than 30 mL/min/1.73m²] [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of glycopyrrolate have not been studied. Glycopyrrolate is cleared predominantly from systemic circulation by renal excretion [see Use in Specific Populations (8.7)].

Glycopyrrolate produced no treatment-related increases in the incidence of tumors in a 2-year inhalation study in Wistar rats at inhaled doses up to 0.56 mg/kg/day approximately 170 times the MRHD on an AUC basis. No evidence of tumorigenicity occurred in a 26-week oral (gavage) study in male and female TgrasH2 mice that received glycopyrrolate at doses up to 93.8 and 125.1 mg/kg/day, respectively.

Glycopyrrolate tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro human lymphocyte chromosomal aberration assay, and in vivo rat bone marrow micronucleus assay.

Impairment of fertility was observed in male and female Wistar rats at a subcutaneous glycopyrrolate dose of 1.88 mg/kg/day (approximately 1,900 and 1,100 times, respectively the MRHD on an AUC basis) based upon findings of decreased implantation sites and corresponding reduction of live fetuses. No effects on fertility and reproductive performance occurred in male and female rats at a subcutaneous glycopyrrolate dose of 0.63 mg/kg/day, approximately 350 times the MRHD on an AUC basis.

Dose selection for glycopyrrolate in COPD was supported by a 28-day, randomized, double-blind, placebo-controlled, 2-period, crossover study evaluating 7 doses of glycopyrrolate (15.6 mcg, 31.2 mcg, 62.4 mcg, and 124.8 mcg once daily and 15.6 mcg, 31.2 mcg, and 62.4 mcg twice daily) or placebo in 388 subjects with COPD. The differences in trough FEV₁ from baseline after 28 days compared to placebo for the 15.6 mcg, 31.2 mcg, 62.4 mcg, and 124.8 mcg once daily and for 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily doses were 0.083 L (95% CI: 0.030, 0.136), 0.098 L (0.048, 0.148), 0.090 L (0.038, 0.142), 0.176 L (0.132, 0.220) 0.139 L (0.089, 0.189), 0.167 L (0.115, 0.219), and 0.177 L (0.132, 0.222), respectively. The dose-ranging results supported the evaluation of glycopyrrolate 15.6 mcg twice daily in the confirmatory COPD trials.

Figure 1. Adjusted Mean Change From Baseline in FEV₁ (L) Over 24 Hours on Days 1 and 28

The clinical development program for SEEBRI NEOHALER included two (Trial 1 and Trial 2) similar 12-week, randomized, double-blinded, placebo-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy of SEEBRI NEOHALER on lung function.

The 12-week trials treated 867 subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a post-bronchodilator FEV₁ greater than or equal to 30% and less than 80% of predicted normal values, had a ratio of FEV₁/FVC of less than 0.7, and were symptomatic as determined by a Modified Medical Research Council (mMRC) score greater than or equal to 2. Of the 867 subjects included in the efficacy analysis, 58% were male and 89% were Caucasian. They had a mean age of 63 years and an average smoking history of 53 pack-years, with 57% identified as current smokers, and 29% using inhaled corticosteroids. At screening, the mean post-bronchodilator percent predicted FEV₁ was 55% (range, 30% to 83%), the mean post-bronchodilator percent FEV₁/FVC was 51% (range, 24% to 69%), and the mean percent reversibility was 20% (0% to 169%).

Trial 1 and Trial 2 evaluated SEEBRI NEOHALER (glycopyrrolate) 15.6 mcg twice daily and placebo twice daily. The primary endpoint was the change from baseline in FEV₁ AUC_0-12h following the morning dose at Day 85 (defined as the mean FEV₁ change from baseline over 0 to 12 hours divided by 12 hours) compared with placebo. In both trials, SEEBRI NEOHALER twice daily demonstrated a larger increase in mean change from baseline in FEV₁ AUC_0-12h compared to placebo (see Table 2).

In Trial 1 and Trial 2, serial spirometric evaluations throughout the 12-hour dosing interval were performed in all subjects at Days 1 and 85. The spirometric curves from Trial 1 at Days 1 and 85 are displayed in Figure 2. In Trial 2, the results for SEEBRI NEOHALER in FEV₁ AUC_0-12h were similar to those observed in Trial 1.

Figure 2. Adjusted Mean Change From Baseline in FEV₁ (L) Over 12 Hours on Days 1 and 85 in Trial 1 (All Patient Population)

The peak FEV₁ was defined as the maximum FEV₁ recorded within 4 hours after the morning dose on Days 1 and 85. The mean peak FEV₁ improvement from baseline for SEEBRI NEOHALER compared with placebo at Day 1 and at Day 85 was 0.142L and 0.163L (Trial 1), and 0.137L and 0.148L (Trial 2), respectively.

In Trials 1 and 2, patients treated with SEEBRI NEOHALER used less daily rescue albuterol during the trial compared to patients treated with placebo.

The St. George's Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2. In Trial 1, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) for the SEEBRI NEOHALER treatment arm was 49% compared to 41% for placebo [Odds Ratio: 1.43, 95% CI: 0.95, 2.15]. In Trial 2, the SGRQ responder rate for the SEEBRI NEOHALER treatment arm was 55% compared to 42% for placebo [Odds Ratio: 1.78; 95% CI: 1.17, 2.71].

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.

Not for Acute Symptoms

Inform patients that SEEBRI NEOHALER is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise them to treat acute symptoms with a rescue inhaler, such as albuterol. Provide patients with such medicine and instruct them in how it should be used [see Warnings and Precautions (5.1)].

Instruct patients to seek medical attention immediately if they experience any of the following:

• Symptoms get worse
• Need for more inhalations than usual of their rescue inhaler

Patients should not stop therapy with SEEBRI NEOHALER without physician/healthcare provider guidance since symptoms may recur after discontinuation.

Paradoxical Bronchospasm

Inform patients that, SEEBRI NEOHALER can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue SEEBRI NEOHALER [see Warnings and Precautions (5.2)].

Worsening of Narrow-Angle Glaucoma

Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g. eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop [see Warnings and Precautions (5.4)].

Worsening of Urinary Retention

Instruct patients to be alert for signs and symptoms of urinary retention (e.g. difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop [see Warnings and Precautions (5.5)].

Instructions for Administering SEEBRI NEOHALER

It is important for patients to understand how to correctly administer SEEBRI capsules using the NEOHALER device [see Instructions for Use]. Instruct patients that SEEBRI capsules should only be administered via the NEOHALER device and the NEOHALER device should not be used for administering other medications. Remind patients that the contents of SEEBRI capsules are for oral inhalation only and must not be swallowed.

Instruct patients always to store SEEBRI capsules in sealed blisters and to only remove a SEEBRI capsule immediately before use or it may not be as effective. Instruct patients to discard unused additional SEEBRI capsules that are exposed to air (i.e., not intended for immediate use).

Inform patients to use one inhalation of SEEBRI NEOHALER orally twice daily (1 capsule in the morning and 1 capsule in the evening) at the same time every day.

Inform patients that if they miss a dose of SEEBRI NEOHALER, they should use their next capsule at the usual time. Instruct patients to not use 2 capsules at one time and to not use more than 2 capsules in a day.

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
T2021-109