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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Immediate hypersensitivity reactions [see Warnings and Precautions (5.2) ] Paradoxical bronchospasm [see Warnings and Precautions (5.3) ] Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4) ] Worsening of urinary retention [see Warnings and Precautions (5.5) ] 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. The most common adverse reactions in: COPD: (>3% incidence in the placebo-controlled trials with treatment durations of between 4 and 48 weeks) were pharyngitis, cough, dry mouth, and sinusitis. ( 6.1 ). Asthma: (>2% incidence in the placebo-controlled trials with treatment durations of between 12 and 52 weeks) were pharyngitis, headache, bronchitis, and sinusitis in adults. ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease The SPIRIVA RESPIMAT 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 6,565 adult COPD patients (75% males and 25% females) 40 years of age and older. Of these patients, 3,282 patients were treated with SPIRIVA RESPIMAT 5 mcg and 3,283 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 FEV 1 of 46%. In these 7 clinical trials, 68.3% of patients exposed to SPIRIVA RESPIMAT 5 mcg reported an adverse event compared to 68.7% of patients in the placebo group. There were 68 deaths in the SPIRIVA RESPIMAT 5 mcg treatment group (2.1%) and 52 deaths (1.6%) in patients who received placebo [see Clinical Studies (14) Long-term Active-Controlled Mortality Trial: Survival ] . The percentage of SPIRIVA RESPIMAT patients who discontinued due to an adverse event were 7.3% compared to 10% with placebo patients. The percentage of SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT 5 mcg treatment group, and a higher incidence rate on SPIRIVA RESPIMAT 5 mcg than on placebo. Table 1 Number (Percentage) of COPD Patients Exposed to SPIRIVA RESPIMAT 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 Body System (Reaction)* SPIRIVA RESPIMAT 5 mcg [n=3,282] Placebo [n=3,283] *Adverse reactions include a grouping of similar terms Gastrointestinal Disorders Dry mouth 134 (4.1) 52 (1.6) Infections and Infestations Pharyngitis 378 (11.5) 333 (10.1) Respiratory, Thoracic, and Mediastinal Disorders Cough 190 (5.8) 182 (5.5) Sinusitis 103 (3.1) 88 (2.7) Other reactions that occurred in the SPIRIVA RESPIMAT 5 mcg group at an incidence of 1% to 3% and at a higher incidence rate on SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT 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. 6.2 Clinical Trials Experience in Asthma Adult Patients SPIRIVA RESPIMAT 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 2,849 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 SPIRIVA RESPIMAT at the recommended dosage 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 (FEV 1 ) of 90.0% at baseline. Table 2 shows all adverse reactions that occurred with an incidence of >2% in the SPIRIVA RESPIMAT 2.5 mcg treatment group, and a higher incidence rate on SPIRIVA RESPIMAT 2.5 mcg than on placebo. Table 2 Number (Percentage) of Asthma Patients Exposed to SPIRIVA RESPIMAT 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 Body System (Reaction)* SPIRIVA RESPIMAT 2.5 mcg [n=787] Placebo [n=735] *Adverse reactions include a grouping of similar terms Respiratory, Thoracic, and Mediastinal Disorders Pharyngitis 125 (15.9) 91 (12.4) Sinusitis 21 (2.7) 10 (1.4) Bronchitis 26 (3.3) 10 (1.4) Nervous System Disorders Headache 30 (3.8) 20 (2.7) Other reactions that occurred in the SPIRIVA RESPIMAT 2.5 mcg group at an incidence of 1% to 2% and at a higher incidence rate on SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT at the recommended dosage 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 FEV 1 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 SPIRIVA RESPIMAT 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 post-bronchodilator percent predicted FEV 1 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. SPIRIVA RESPIMAT 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 4,149 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 (1,370 adults and 264 adolescents receiving SPIRIVA RESPIMAT 5 mcg once-daily). The adverse reaction profile for SPIRIVA RESPIMAT 5 mcg in patients with asthma was comparable to that observed with SPIRIVA RESPIMAT 2.5 mcg in patients with asthma. 6.3 Postmarketing Experience In addition to the adverse reactions observed during the SPIRIVA RESPIMAT 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.