Norvent

Maintenance Treatment Of Chronic Obstructive Pulmonary Disease

Norvent (tiotropium bromide) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Norvent is indicated to reduce exacerbations in COPD patients.

Important Limitation Of Use

Norvent is NOT indicated for the relief of acute bronchospasm.

Maintenance Treatment Of Asthma

Norvent is a bronchodilator indicated for the long-term, once-daily, maintenance treatment of asthma in patients 6 years of age and older.

Important Limitation Of Use

Norvent is NOT indicated for the relief of acute bronchospasm.

Norvent HANDIHALER (tiotropium bromide inhalation powder) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Norvent HANDIHALER is indicated to reduce exacerbations in COPD patients.

To receive the full dose of medication, Norvent must be administered as two inhalations once-daily. Do not take more than one dose (2 inhalations) in 24 hours.

Prior to first use, the SPIRIVA RESPIMAT cartridge is inserted into the Norvent inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.

Chronic Obstructive Pulmonary Disease

The recommended dosage for patients with COPD is 2 inhalations of Norvent 2.5 mcg per actuation once-daily; total dose equals 5 mcg of Norvent.

Asthma

The recommended dosage for patients with asthma is 2 inhalations of Norvent 1.25 mcg per actuation once-daily; total dose equals 2.5 mcg of Norvent. In the treatment of asthma, the maximum benefits in lung function may take up to 4 to 8 weeks of dosing.

Special Populations

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given SPIRIVA RESPIMAT should be monitored closely for anticholinergic effects.

For oral inhalation only. Do not swallow Norvent capsules, as the intended effects on the lungs will not be obtained. The contents of the Norvent capsules should only be used with the HANDIHALER device

The recommended dose of Norvent HANDIHALER is two inhalations of the powder contents of one Norvent capsule, once-daily, with the HANDIHALER device. Do not take more than one dose in 24 hours.

For administration of Norvent HANDIHALER, a Norvent capsule is placed into the center chamber of the HANDIHALER device. The Norvent capsule is pierced by pressing and releasing the green piercing button on the side of the HANDIHALER device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given Norvent HANDIHALER should be monitored closely for anticholinergic effects.

Norvent is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any component of this product. In clinical trials with Norvent, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported.

Norvent HANDIHALER is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product. In clinical trials and postmarketing experience with Norvent HANDIHALER, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Not For Acute Use

Norvent is intended as a once-daily maintenance treatment for COPD and asthma and should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. In the event of an acute attack, a rapid-acting beta2-agonist should be used.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of Norvent. If such a reaction occurs, therapy with Norvent should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to Norvent.

Paradoxical Bronchospasm

Inhaled medicines, including Norvent, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-acting beta2-agonist such as albuterol. Treatment with Norvent should be stopped and other treatments considered.

Worsening Of Narrow-Angle Glaucoma

Norvent 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.

Worsening Of Urinary Retention

Norvent 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.

Renal Impairment

As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of < 60 mL/min) treated with Norvent should be monitored closely for anticholinergic side effects.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

Not For Acute Use

Instruct patients that Norvent is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems, (i.e., as a rescue medication).

Immediate Hypersensitivity Reactions

Inform patients that anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, may occur after administration of Norvent. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.

Paradoxical Bronchospasm

Inform patients that Norvent can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Norvent.

Worsening Of Narrow-Angle Glaucoma

Instruct patients to be alert for signs and symptoms of 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 and symptoms develop.

Inform patients that care must be taken not to allow the aerosol cloud to enter into the eyes as this may cause blurring of vision and pupil dilation.

Since dizziness and blurred vision may occur with the use of Norvent, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.

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.

Treatment Of Asthma

Instruct asthma patients that the maximum benefits may only be apparent after 4 to 8 weeks of Norvent treatment.

Instructions For Administering Norvent

It is important for patients to understand how to correctly administer SPIRIVA inhalation spray using the Norvent inhaler. Instruct patients that SPIRIVA inhalation spray should only be administered via the Norvent inhaler and the Norvent inhaler should not be used for administering other medications.

Instruct patients that priming Norvent is essential to ensure appropriate content of the medication in each actuation.

When using the unit for the first time, the SPIRIVA RESPIMAT cartridge is inserted into the Norvent inhaler and the unit is primed. Norvent patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then to repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.

Instruct caregivers of children that Norvent should be used with an adult's assistance.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female mice at doses up to 145 mcg/kg/day, and in a 101-week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40, and 0.5, times the maximum recommended human daily inhalation dose (MRHDID) on a mcg/m² basis, respectively.

Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA synthesis in primary rat hepatocytes in vitro assay.

In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day or greater (approximately 40 times the MRHDID on a mcg/m² basis). No such effects were observed at 9 mcg/kg/day (approximately 5 times the MRHDID on a mcg/m² basis). The fertility index, however, was not affected at inhalation doses up to 1689 mcg/kg/day (approximately 910 times the MRHDID on a mcg/m² basis).

Use In Specific Populations

Pregnancy

Risk Summary

The limited human data with Norvent use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. There are risks to the mother and the fetus associated with poorly controlled asthma in pregnancy. Based on animal reproduction studies, no structural abnormalities were observed when tiotropium was administered by inhalation to pregnant rats and rabbits during the period of organogenesis at doses 790 and 8 times, respectively, the maximum recommended human daily inhalation dose (MRHDID). Increased post-implantation loss was observed in rats and rabbits administered tiotropium at maternally toxic doses 430 times and 40 times the MRHDID, respectively.

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

Disease-Associated Maternal and/or Embryo-Fetal Risk

Poorly or moderately controlled asthma in pregnancy increases the maternal risk of preeclampsia and infant prematurity, low birth weight, and small for gestational age. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.

Data

Animal Data

In 2 separate embryo-fetal development studies, pregnant rats and rabbits received tiotropium during the period of organogenesis at doses up to approximately 790 and 8 times the maximum recommended human daily inhalation dose (MRHDID), respectively (on a mcg/m² basis at inhalation doses of 1471 and 7 mcg/kg/day in rats and rabbits, respectively). No evidence of structural abnormalities was observed in rats or rabbits. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at tiotropium doses of approximately 40 times the MRHDID (on a mcg/m² basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at a tiotropium dose of approximately 430 times the MRHDID (on a mcg/m² basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the MRHDID, respectively (on a mcg/m² basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).

Lactation

Risk Summary

There are no data on the presence of tiotropium in human milk, the effects on the breastfed infant, or the effects on milk production. Tiotropium is present in milk of lactating rats; however, due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Norvent and any potential adverse effects on the breastfed child from Norvent or from the underlying maternal condition.

Data

The distribution of tiotropium bromide into milk was investigated after a single intravenous administration of 10 mg/kg to lactating rats. Tiotropium and/or its metabolites are present in the milk of lactating rats at concentrations above those in plasma.

Pediatric Use

The safety and efficacy of Norvent 2.5 mcg have been established in pediatric patients aged 6 to 17 years with asthma in 6 clinical trials up to 1 year in duration. In three clinical trials, 327 patients aged 12 to 17 years with asthma were treated with Norvent 2.5 mcg; in three additional clinical trials, 345 patients aged 6 to 11 years with asthma were treated with Norvent 2.5 mcg. Patients in these age groups demonstrated efficacy results similar to those observed in patients aged 18 years and older with asthma.

The safety and efficacy of Norvent have not been established in pediatric patients less than 6 years of age. The safety of Norvent 2.5 mcg has been studied in pediatric patients with asthma aged 1 to 5 years who were on background treatment of at least ICS in one placebo-controlled clinical trial of 12 weeks duration (36 treated with SPIRIVA RESPIMAT 2.5 mcg and 34 with placebo RESPIMAT). In this study, Norvent or placebo RESPIMAT was delivered with the AeroChamber Plus Flow-Vu^® valved holding chamber with facemask once daily. The majority of the patients in the trial were male (60.4%) and Caucasian (76.2%) with a mean age of 3.1 years. The adverse reaction profile was similar to that observed in adults and older pediatric patients.

In Vitro Characterization Studies With Valved Holding Chamber

Dose delivery and fine particle fraction of SPIRIVA RESPIMAT when administered via a valved holding chamber (AeroChamber Plus Flow-Vu® with or without face mask) was assessed by in vitro studies.

Inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds were tested. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively.

Table 3 summarizes the results for delivered dose under the respective test conditions and configurations.

Table 3 : In Vitro Medication Delivery through AeroChamber Plus Flow-Vu® Valved Holding Chamber with Face Mask at Different low Rates and Holding Times Using the Dose 2.5 mcg (as two actuations)

The in vitro study data show a reduction of the absolute delivered dose through the valved holding chamber. However, in terms of dose per kilogram of body weight the data suggest that under all tested conditions the dose of Norvent delivered by the AeroChamber Plus Flow-Vu® valved holding chamber with mask will at least lead to a dosing comparable to that of adults without use of a holding chamber and mask (Table 3). The fine particle fraction ( < 5 μm) across the flow rates used in these studies was 69-89% of the delivered dose through the valved holding chamber, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for Norvent delivered without a holding chamber typically represents approximately 60% of the delivered dose.

Geriatric Use

Based on available data, no adjustment of Norvent dosage in geriatric patients is warranted.

Thirty nine percent of SPIRIVA RESPIMAT clinical trial patients with COPD were between 65 and 75 years of age and 14% were greater than or equal to 75 years of age. Approximately seven percent of Norvent clinical trial patients with asthma were greater than or equal to 65 years of age. The adverse drug reaction profiles were similar in the older population compared to the patient population overall.

Renal Impairment

Patients with moderate to severe renal impairment (creatinine clearance of < 60 mL/min) treated with Norvent should be monitored closely for anticholinergic side effects.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Not For Acute Use

Norvent HANDIHALER is intended as a once-daily maintenance treatment for COPD and should not be used for relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching, may occur after administration of Norvent HANDIHALER. If such a reaction occurs, therapy with Norvent HANDIHALER should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to Norvent HANDIHALER. In addition, Norvent HANDIHALER should be used with caution in patients with severe hypersensitivity to milk proteins.

Paradoxical Bronchospasm

Inhaled medicines, including Norvent HANDIHALER, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled shortacting beta2-agonist such as albuterol. Treatment with Norvent HANDIHALER should be stopped and other treatments considered.

Worsening Of Narrow-Angle Glaucoma

Norvent HANDIHALER 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.

Worsening Of Urinary Retention

Norvent HANDIHALER 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.

Renal Impairment

As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of < 60 mL/min) treated with Norvent HANDIHALER should be monitored closely for anticholinergic side effects.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Paradoxical Bronchospasm

Inform patients that Norvent HANDIHALER can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Norvent HANDIHALER.

Worsening of Narrow-Angle Glaucoma

Instruct patients to be alert for signs and symptoms of 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 and symptoms develop.

Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.

Since dizziness and blurred vision may occur with the use of Norvent HANDIHALER, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.

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.

Not for Acute Use

Instruct patients that Norvent HANDIHALER is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

Instructions for Administering Norvent HANDIHALER

Instruct patients on how to correctly administer Norvent capsules using the HANDIHALER device. Instruct patients that Norvent capsules should only be administered via the HANDIHALER device and the HANDIHALER device should not be used for administering other medications. Remind patients that the contents of Norvent capsules are for oral inhalation only and must not be swallowed.

Instruct patients always to store Norvent capsules in sealed blisters and to remove only one Norvent capsule immediately before use or its effectiveness may be reduced. Instruct patients to discard unused additional Norvent capsules that are exposed to air (i.e., not intended for immediate use).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female mice at doses up to 145 mcg/kg/day, and in a 101-week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40, and 0.5 times the recommended human daily inhalation dose (MRHDID) on a mcg/m² basis, respectively.

Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA synthesis in primary rat hepatocytes in vitro assay.

In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day or greater (approximately 40 times the MRHDID on a mcg/m² basis). No such effects were observed at 9 mcg/kg/day (approximately 5 times the MRHDID on a mcg/m² basis). The fertility index, however, was not affected at inhalation doses up to 1689 mcg/kg/day (approximately 910 times the MRHDID on a mcg/m² basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C.

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

No evidence of structural alterations was observed in rats and rabbits at approximately 790 and 8 times the maximum recommended human daily inhalation dose (MRHDID), respectively (on a mcg/m² basis at maternal inhalation doses of 1471 and 7 mcg/kg/day in rats and rabbits, respectively). However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at inhalation tiotropium doses of approximately 40 times the MRHDID (on a mcg/m² basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in postimplantation loss at an inhalation dose of approximately 430 times the MRHDID (on a mcg/m² basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at inhalation doses of approximately 5 and 95 times the MRHDID, respectively (on a mcg/m² basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).

Labor And Delivery

The safety and effectiveness of Norvent HANDIHALER has not been studied during labor and delivery.

Nursing Mothers

Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if Norvent HANDIHALER is administered to a nursing woman.

Pediatric Use

Norvent HANDIHALER is not indicated for use in children. The safety and effectiveness of Norvent HANDIHALER in pediatric patients have not been established.

Geriatric Use

Based on available data, no adjustment of Norvent HANDIHALER dosage in geriatric patients is warranted.

Of the total number of patients who received Norvent HANDIHALER in the 1-year clinical trials, 426 were < 65 years, 375 were 65 to 74 years, and 105 were ≥ 75 years of age. Within each age subgroup, there were no differences between the proportion of patients with adverse events in the Norvent HANDIHALER and the comparator groups for most events. Dry mouth increased with age in the Norvent HANDIHALER group (differences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A higher frequency of constipation and urinary tract infections with increasing age was observed in the Norvent HANDIHALER group in the placebo-controlled studies. The differences from placebo for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these groups.

Renal Impairment

Patients with moderate to severe renal impairment (creatinine clearance of < 60 mL/min) treated with Norvent HANDIHALER should be monitored closely for anticholinergic side effects.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

The following adverse reactions are described, or described in greater detail, in other sections:

• Immediate hypersensitivity reactions
• Paradoxical bronchospasm
• Worsening of narrow-angle glaucoma
• Worsening of urinary retention

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

Since the same active ingredient (tiotropium bromide) is administered to COPD and asthma patients, prescribers and patients should take into account that the observed adverse reactions could be relevant for both patient populations independent of dosage strength.

Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

The Norvent clinical development program included ten placebo controlled clinical trials in COPD. Two trials were four-week cross-over trials and eight were parallel group trials. The parallel group trials included a three week dose-ranging trial, two 12-week trials, three 48-week trials, and two trials of 4-week and 24-week duration conducted for a different program that contained tiotropium bromide 5 mcg treatment arms. The primary safety database consists of pooled data from the 7 randomized, parallel-group, double-blind, placebo-controlled studies of 4-48 weeks in treatment duration. These trials included 6565 adult COPD patients (75% males and 25% females) 40 years of age and older. Of these patients, 3282 patients were treated with Norvent 5 mcg and 3283 received placebo. The SPIRIVA RESPIMAT 5 mcg group was composed mostly of Caucasians (78%) with a mean age of 65 years and a mean baseline percent predicted post-bronchodilator FEV₁ of 46%.

In these 7 clinical trials, 68.3% of patients exposed to Norvent 5 mcg reported an adverse event compared to 68.7% of patients in the placebo group. There were 68 deaths in the Norvent 5 mcg treatment group (2.1%) and 52 deaths (1.6%) in patients who received placebo. The percentage of Norvent patients who discontinued due to an adverse event were 7.3% compared to 10% with placebo patients. The percentage of Norvent 5 mcg patients who experienced a serious adverse event were 15.0% compared to 15.1% with placebo patients. In both groups, the adverse event most commonly leading to discontinuation was COPD exacerbation (SPIRIVA RESPIMAT 2.0%, placebo 4.0%) which was also the most frequent serious adverse event. The most commonly reported adverse reactions were pharyngitis, cough, dry mouth, and sinusitis (Table 1). Other adverse reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, dysuria, and urinary retention.

Table 1 shows all adverse reactions that occurred with an incidence of > 3% in the Norvent 5 mcg treatment group, and a higher incidence rate on Norvent 5 mcg than on placebo.

Table 1 : Number (Percentage) of COPD Patients Exposed to Norvent 5 mcg with Adverse Reactions > 3% (and Higher than Placebo): Pooled Data from 7 Clinical Trials with Treatment Periods Ranging between 4 and 48 Weeks in COPD Patients

Other reactions that occurred in the Norvent 5 mcg group at an incidence of 1% to 3% and at a higher incidence rate on Norvent 5 mcg than on placebo included: Cardiac disorders: palpitations; Gastrointestinal disorders: constipation, gastroesophageal reflux disease, oropharyngeal candidiasis; Nervous system disorders: dizziness; Respiratory, thoracic, and mediastinal disorders: dysphonia; Skin and subcutaneous tissue disorders: pruritus, rash; Renal and urinary disorders: urinary tract infection.

Less Common Adverse Reactions

Among the adverse reactions observed in the clinical trials with an incidence of < 1% and at a higher incidence rate on Norvent 5 mcg than on placebo were: dysphagia, gingivitis, intestinal obstruction including ileus paralytic, joint swelling, dysuria, urinary retention, epistaxis, laryngitis, angioedema, dry skin, skin infection, and skin ulcer.

Clinical Trials Experience In Asthma

Adult Patients

Norvent 2.5 mcg has been compared to placebo in four placebo-controlled parallel-group trials ranging from 12 to 52 weeks of treatment duration in adult patients (aged 18 to 75 years) with asthma. The safety data described below are based on one 1-year, two 6-month and one 12-week randomized, double-blind, placebo-controlled trials in a total of 2849 asthma patients on background treatment of at least ICS or ICS and long-acting beta agonist (ICS/LABA). Of these patients, 787 were treated with Norvent at the recommended dose of 2.5 mcg once-daily; 59.7% were female and 47.5% were Caucasian with a mean age of 43.7 years and a mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV₁) of 90.0% at baseline.

Table 2 shows all adverse reactions that occurred with an incidence of > 2% in the Norvent 2.5 mcg treatment group, and a higher incidence rate on Norvent 2.5 mcg than on placebo.

Table 2 : Number (Percentage) of Asthma Patients Exposed to Norvent 2.5 mcg with Adverse Reactions > 2% (and Higher than Placebo): Pooled Data from 4 Adult Clinical Trials with Treatment Periods Ranging between 12 and 52 Weeks in Asthma Patients

Other reactions that occurred in the Norvent 2.5 mcg group at an incidence of 1% to 2% and at a higher incidence rate on Norvent 2.5 mcg than on placebo included: Nervous system disorders: dizziness; Gastrointestinal disorders: oropharyngeal candidiasis, diarrhea; Respiratory, thoracic, and mediastinal disorders: cough, rhinitis allergic; Renal and urinary disorders: urinary tract infection; General disorders and administration site conditions: pyrexia; and Vascular disorders: hypertension.

Less Common Adverse Reactions

Among the adverse reactions observed in the clinical trials with an incidence of 0.5% to < 1% and at a higher incidence rate on Norvent 2.5 mcg than on placebo were: palpitations, dysphonia, acute tonsillitis, tonsillitis, rhinitis, herpes zoster, gastroesophageal reflux disease, oropharyngeal discomfort, abdominal pain upper, insomnia, hypersensitivity (including immediate reactions), angioedema, dehydration, arthralgia, muscle spasms, pain in extremity, chest pain, hepatic function abnormal, liver function test abnormal.

Adolescent Patients Aged 12 To 17 years

Norvent 2.5 mcg has been compared to placebo in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in adolescent patients with asthma. The safety data described below are based on one 48-week and one 12-week double-blind, placebo-controlled trials in a total of 789 adolescent asthma patients on background treatment of at least ICS or ICS plus one or more controller. Of these patients, 252 were treated with Norvent at the recommended dose of 2.5 mcg once-daily; 63.9% were male and 95.6% were Caucasian with a mean age of 14.3 years and a mean post-bronchodilator percent predicted FEV₁ of 98.3% at baseline. The adverse reaction profile for adolescent patients with asthma was comparable to that observed in adult patients with asthma.

Pediatric Patients Aged 6 To 11 years

Norvent 2.5 mcg has been compared to placebo in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in pediatric patients aged 6 to 11 years with asthma. The safety data are based on one 48-week and one 12-week double-blind, placebo-controlled trials in a total of 801 pediatric asthma patients aged 6 to 11 years on background treatment of at least ICS or ICS plus one or more controller. Of these patients, 271 were treated with SPIRIVA RESPIMAT at the recommended dose of 2.5 mcg once-daily; 71.2% were male and 86.7% were Caucasian with a mean age of 8.9 years and a mean postbronchodilator percent predicted FEV₁ of 97.9% at baseline. The adverse reaction profile for pediatric patients aged 6 to 11 years with asthma was comparable to that observed in adult patients with asthma.

Norvent 5 mcg also has been compared to placebo in seven placebo-controlled parallel-group trials ranging from 12 to 52 weeks of treatment duration in 4149 adult patients (aged 18 to 75 years) with asthma and in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in 789 adolescent patients (1370 adults and 264 adolescents receiving Norvent 5 mcg once-daily). The adverse reaction profile for Norvent 5 mcg in patients with asthma was comparable to that observed with Norvent 2.5 mcg in patients with asthma.

Postmarketing Experience

In addition to the adverse reactions observed during the Norvent clinical trials in COPD, the following adverse reactions have been observed during post-approval use of SPIRIVA RESPIMAT 5 mcg and another tiotropium formulation, SPIRIVA® HandiHaler® (tiotropium bromide inhalation powder). 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.

• Glaucoma, intraocular pressure increased, vision blurred,
• Atrial fibrillation, tachycardia, supraventricular tachycardia,
• Bronchospasm,
• Glossitis, stomatitis,
• Dehydration,
• Insomnia,
• Hypersensitivity (including immediate reactions), and urticaria.

The following adverse reactions are described, or described in greater detail, in other sections:

• Immediate hypersensitivity reactions
• Paradoxical bronchospasm
• Worsening of narrow-angle glaucoma
• Worsening of urinary retention

Clinical Trials Experience

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

6-Month to 1-Year Trials

The data described below reflect exposure to Norvent HANDIHALER in 2663 patients. Norvent HANDIHALER was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with Norvent HANDIHALER at the recommended dose of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV₁) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database because only serious adverse events were collected.

The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention.

Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated Norvent HANDIHALER in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥ 3% in the Norvent HANDIHALER group in the 1-year placebo-controlled trials where the rates in the Norvent HANDIHALER group exceeded placebo by ≥ 1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison.

Table 1 : Adverse Reactions (% Patients) in One-Year COPD Clinical Trials

Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥ 3% in the Norvent HANDIHALER treatment group, but were < 1% in excess of the placebo group.

Other reactions that occurred in the Norvent HANDIHALER group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical trials with an incidence of < 1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention.

In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age.

Two multicenter, 6-month, controlled studies evaluated Norvent HANDIHALER in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials.

4-Year Trial

The data described below reflect exposure to Norvent HANDIHALER in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2986 patients were treated with Norvent HANDIHALER at the recommended dose of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator FEV₁ percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. When the adverse reactions were analyzed with a frequency of ≥ 3% in the Norvent HANDIHALER group where the rates in the Norvent HANDIHALER group exceeded placebo by ≥ 1%, adverse reactions included (Norvent HANDIHALER, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%).

Additional Adverse Reactions

Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with Norvent HANDIHALER than placebo include: dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling.

Postmarketing Experience

Adverse reactions have been identified during worldwide post-approval use of Norvent HANDIHALER. 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: application site irritation (glossitis, mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria.

High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium dry powder in 6 healthy volunteers. Dry mouth/throat and dry nasal mucosa occurred in a dose-dependent [10-40 mcg daily] manner, following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects.

Treatment of overdosage consists of discontinuation of Norvent together with institution of appropriate symptomatic and/or supportive therapy.

High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated oncedaily inhalation of 141 mcg of tiotropium.

Treatment of overdosage consists of discontinuation of Norvent HANDIHALER together with institution of appropriate symptomatic and/or supportive therapy.

Accidental Ingestion

Acute intoxication by inadvertent oral ingestion of Norvent capsules is unlikely since it is not well-absorbed systemically.

A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, Norvent HANDIHALER was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day.

Cardiac Electrophysiology

In a multicenter, randomized, double-blind trial using tiotropium dry powder for inhalation that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the SPIRIVA group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs. 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs. 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of > 500 msec. Other clinical trials with SPIRIVA did not detect an effect of the drug on QTc intervals.

The effect of tiotropium dry powder for inhalation on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received tiotropium inhalation powder 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for tiotropium inhalation powder 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc > 500 msec or QTc changes from baseline of ≥ 60 msec.

Cardiac Electrophysiology

In a multicenter, randomized, double-blind trial using tiotropium dry powder for inhalation that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the Norvent HANDIHALER group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs. 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs. 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of > 500 msec. Other clinical studies with Norvent HANDIHALER did not detect an effect of the drug on QTc intervals.

The effect of tiotropium dry powder for inhalation on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received tiotropium dry powder for inhalation 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for tiotropium dry powder for inhalation 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc > 500 msec or QTc changes from baseline of ≥ 60 msec.

Tiotropium is administered as an inhalation spray. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. A dedicated pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the RESPIMAT inhaler (5 mcg) and as inhalation powder (18 mcg) from the HandiHaler resulted in a similar systemic exposure between the two products.

Absorption

Following inhalation of the solution by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Food is not expected to influence the absorption of tiotropium for the same reason. Following 4-week Norvent once daily dosing, maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation in COPD and asthma patients.

Distribution

The drug has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg after an intravenous dose to young healthy volunteers. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier.

Elimination

Metabolism

The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors.

In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

Excretion

The terminal half-life of tiotropium in COPD and asthma patients following once daily inhalation is 25 and 44 hours, respectively. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). Following 21-day once daily inhalation of 5 mcg of the solution by patients with COPD, 24-hour urinary excretion is 18.6% (0.93 mcg) of the dose. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. In comparison, 12.8% (0.32 mcg) of the dose was excreted unchanged in the urine over 24 hours at steady state after inhalation of 2.5 mcg in patients with asthma. After chronic once-daily inhalation by COPD and asthma patients, pharmacokinetic steady-state was reached by day 7 with no accumulation thereafter.

Tiotropium is administered by dry powder inhalation. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. A dedicated pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the RESPIMAT inhaler (5 mcg) and as inhalation powder (18 mcg) from the HANDIHALER device resulted in a similar systemic exposure between the two products.

Absorption

Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of tiotropium. Maximum tiotropium plasma concentrations were observed 7 minutes after inhalation.

Distribution

Tiotropium is 72% bound to plasma protein and had a volume of distribution of 32 L/kg after intravenous administration to young healthy volunteers. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not readily penetrate the blood-brain barrier.

Elimination

The terminal half-life of tiotropium in COPD patients following once daily inhalation of 5 mcg tiotropium was approximately 25 hours. Total clearance was 880 mL/min after intravenous administration in young healthy volunteers. After chronic once-daily dry powder inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.

Metabolism

The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors.

In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

Excretion

Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After dry powder inhalation to COPD patients at steady state, urinary excretion was 7% (1.3 μg) of the unchanged dose over 24 hours. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine.