Tiotropium Bromide Drug Information
Generic name: TIOTROPIUM BROMIDE
Uses of Tiotropium Bromide
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. Tiotropium bromide inhalation powder is indicated to reduce exacerbations in COPD patients. Tiotropium bromide inhalation powder is an anticholinergic indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), and for reducing COPD exacerbations
Dosage & Administration of Tiotropium Bromide
For oral inhalation only. Do not swallow tiotropium bromide inhalation powder capsules, as the intended effects on the lungs will not be obtained. The contents of the tiotropium bromide inhalation powder capsules should only be used with the LupinHaler ® device . The recommended dosage of tiotropium bromide inhalation powder is two inhalations of the powder contents of one tiotropium bromide inhalation powder capsule, once-daily, with the LupinHaler device.
Do not take more than one dose in 24 hours. For administration of tiotropium bromide inhalation powder, a tiotropium bromide inhalation powder capsule is placed into the center chamber of the LupinHaler device. The tiotropium bromide inhalation powder capsule is pierced by pressing and releasing the green piercing button on the side of the LupinHaler 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 tiotropium bromide inhalation powder should be monitored closely for anticholinergic effects.
For oral inhalation only. DO NOT swallow tiotropium bromide inhalation powder capsules. Only use tiotropium bromide inhalation powder capsules with the LupinHaler ® device Two inhalations of the powder contents of a single tiotropium bromide inhalation powder capsule (18 mcg) once daily
Side Effects of Tiotropium Bromide
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 tiotropium bromide inhalation powder in 2,663 patients. Tiotropium bromide inhalation powder 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, 1,308 patients were treated with tiotropium bromide inhalation powder at the recommended dosage 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 (FEV 1 ) 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 tiotropium bromide inhalation powder in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the tiotropium bromide inhalation powder group in the 1-year placebo-controlled trials where the rates in the tiotropium bromide inhalation powder 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 Body System (Event) Placebo-Controlled Trials Ipratropium-Controlled Trials Tiotropium Bromide Inhalation Powder (n = 550) Placebo (n = 371) Tiotropium Bromide Inhalation Powder (n = 356) Ipratropium (n = 179) Body as a Whole Chest Pain (non-specific) 7 5 5 2 Edema, Dependent 5 4 3 5 Gastrointestinal System Disorders Dry Mouth 16 3 12 6 Dyspepsia 6 5 1 1 Abdominal Pain 5 3 6 6 Constipation 4 2 1 1 Vomiting 4 2 1 2 Musculoskeletal System Myalgia 4 3 4 3 Resistance Mechanism Disorders Infection 4 3 1 3 Moniliasis 4 2 3 2 Respiratory System (Upper) Upper Respiratory Tract Infection 41 37 43 35 Sinusitis 11 9 3 2 Pharyngitis 9 7 7 3 Rhinitis 6 5 3 2 Epistaxis 4 2 1 1 Skin and Appendage Disorders Rash 4 2 2 2 Urinary System Urinary Tract Infection 7 5 4 2 Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the tiotropium bromide inhalation powder treatment group, but were <1% in excess of the placebo group.
Other reactions that occurred in the tiotropium bromide inhalation powder 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 tiotropium bromide inhalation powder 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 tiotropium bromide inhalation powder in 5,992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2,986 patients were treated with tiotropium bromide inhalation powder at the recommended dosage 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 FEV 1 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 tiotropium bromide inhalation powder group where the rates in the tiotropium bromide inhalation powder group exceeded placebo by ≥1%, adverse reactions included (tiotropium bromide inhalation powder, 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 tiotropium bromide inhalation powder 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
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. 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.
Warnings & Cautions for Tiotropium Bromide
Not for Acute Use Tiotropium bromide inhalation powder 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 tiotropium bromide inhalation powder. If such a reaction occurs, therapy with tiotropium bromide inhalation powder 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 tiotropium bromide inhalation powder.
In addition, tiotropium bromide inhalation powder should be used with caution in patients with severe hypersensitivity to milk proteins.
Paradoxical Bronchospasm Inhaled medicines, including tiotropium bromide inhalation powder, may cause paradoxical
bronchospasm. If this occurs, it should be treated immediately with an inhaled short- acting beta 2 -agonist such as albuterol. Treatment with tiotropium bromide inhalation powder should be stopped and other treatments considered.
Worsening of Narrow-Angle Glaucoma Tiotropium bromide inhalation powder 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 Tiotropium bromide inhalation powder 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 tiotropium bromide inhalation powder should be monitored closely for anticholinergic side effects.
Drug Interactions with Tiotropium Bromide
Sympathomimetics, Methylxanthines, Steroids Tiotropium bromide inhalation powder has been used concomitantly with
short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse reactions.
Anticholinergics
There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of tiotropium bromide inhalation powder with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.
Pregnancy Safety for Tiotropium Bromide
Pregnancy Risk Summary The limited human data with tiotropium bromide inhalation powder use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. 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. 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 MRHDID, respectively (on a mcg/m 2 basis at inhalation doses of 1,471 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/m 2 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/m 2 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/m 2 basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).
Pediatric Use of Tiotropium Bromide
Pediatric Use Tiotropium bromide inhalation powder is not indicated for use in children. The safety and effectiveness of tiotropium bromide inhalation powder in pediatric patients have not been established.
Contraindications for Tiotropium Bromide
Tiotropium bromide inhalation powder is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product . In clinical trials and postmarketing experience with tiotropium bromide inhalation powder, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported . Hypersensitivity to tiotropium, ipratropium, or any components of tiotropium bromide inhalation powder capsules
Overdosage Information for Tiotropium Bromide
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 once- daily inhalation of 141 mcg of tiotropium.
Treatment of overdosage consists of discontinuation of tiotropium bromide inhalation powder together with institution of appropriate symptomatic and/or supportive therapy. Accidental Ingestion Acute intoxication by inadvertent oral ingestion of tiotropium bromide inhalation powder 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, tiotropium bromide inhalation powder was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day.
Clinical Studies of Tiotropium Bromide
The tiotropium bromide inhalation powder clinical development program consisted of six Phase 3 studies in 2,663 patients with COPD (1,308 receiving tiotropium bromide inhalation powder): two 1-year, placebo-controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These studies enrolled patients who 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 forced expiratory volume in one second (FEV 1 ) less than or equal to 60% or 65% of predicted, and a ratio of FEV 1 /FVC of less than or equal to 0.7. In these studies, tiotropium bromide inhalation powder, administered once-daily in the morning, provided improvement in lung function (FEV 1 ), with peak effect occurring within 3 hours following the first dose. Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1,829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5,992 COPD patients.
Long-term effects on lung function and other outcomes, were also evaluated in the 4-year multicenter trial. 6-Month to 1-Year Effects on Lung Function In the 1-year, placebo-controlled trials, the mean improvement in FEV 1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1). Further improvements in FEV 1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The mean peak improvement in FEV 1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance.
In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial FEV 1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV 1 ) with tiotropium bromide inhalation powder, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month treatment period. Figure 1 : Mean FEV 1 Over Time (prior to and after administration of study drug) on Days 1 and 169 for Trial A (a Six-Month Placebo-Controlled Study)* *Means adjusted for center, treatment, and baseline effect.
On Day 169, a total of 183 and 149 patients in the tiotropium bromide inhalation powder and placebo groups, respectively, completed the trial. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward. Results of each of the 1-year ipratropium-controlled trials were similar to the results of the 1-year placebo-controlled trials.
The results of one of these trials are shown in Figure 2. Figure 2 : Mean FEV 1 Over Time (0 to 6 hours post-dose) on Days 1 and 92, Respectively for One of the Two Ipratropium-Controlled Studies* *Means adjusted for center, treatment, and baseline effect. On Day 92 (primary endpoint), a total of 151 and 69 patients in the tiotropium bromide inhalation powder and ipratropium groups, respectively, completed through 3 months of observation. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward.
A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, regardless of whether tiotropium bromide inhalation powder was administered in the morning or in the evening. Throughout each week of the 1-year treatment period in the two placebo-controlled trials, patients taking tiotropium bromide inhalation powder had a reduced requirement for the use of rescue short-acting beta 2 -agonists. Reduction in the use of rescue short-acting beta 2 -agonists, as compared to placebo, was demonstrated in one of the two 6 -month studies. 4-Year Effects on Lung Function A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5,992 COPD patients was conducted to evaluate the long-term effects of tiotropium bromide inhalation powder on disease progression (rate of decline in FEV 1 ). Patients were permitted to use all respiratory medications (including short-acting and long- acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics.
The patients were 40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV 1 of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV 1, as demonstrated by similar slopes of FEV 1 decline over time (Figure 3). Tiotropium bromide inhalation powder maintained improvements in trough (pre-dose) FEV 1 (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study (Figure 3). Figure 3 : Trough (pre-dose) FEV 1 Mean Values at Each Time Point Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements.
Baseline trough FEV 1 (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary function tests after Day 30 and non-missing baseline value were included in the analysis. Exacerbations The effect of tiotropium bromide inhalation powder on COPD exacerbations was evaluated in two clinical trials: a 4-year clinical trial described above and a 6-month clinical trial of 1,829 COPD patients in a Veterans Affairs setting. In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization.
The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre -bronchodilator FEV 1 percent predicted of 36% (range = 8% to 93%). Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. Tiotropium bromide inhalation powder significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo (27.9% vs. 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99; p = 0.037). The proportion of patients with hospitalization due to COPD exacerbations in patients who used tiotropium bromide inhalation powder compared to placebo was 7.0% vs. 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056. Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial.
In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. Tiotropium bromide inhalation powder significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; p<0.002) compared to placebo. The median time to first exacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8) in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the tiotropium bromide inhalation powder group.
All-Cause Mortality In the 4-year placebo-controlled lung-function trial described above, all-cause mortality compared to placebo was assessed. There were no significant differences in all- cause mortality rates between tiotropium bromide inhalation powder and placebo. The all-cause mortality of tiotropium bromide inhalation powder was also compared to tiotropium inhalation spray 5 mcg (SPIRIVA RESPIMAT ® 5 mcg) in an additional long-term, randomized, double-blind, double-dummy active-controlled study with an observation period up to 3 years.
All-cause mortality was similar between tiotropium bromide inhalation powder and SPIRIVA RESPIMAT ®. Image Image Image
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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