Spiriva Drug Information
Generic name: TIOTROPIUM BROMIDE INHALATION SPRAY
Uses of Spiriva
Maintenance Treatment of Chronic Obstructive Pulmonary Disease
SPIRIVA RESPIMAT (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. SPIRIVA RESPIMAT is indicated to reduce exacerbations in COPD patients. Important Limitation of Use: SPIRIVA RESPIMAT is NOT indicated for the relief of acute bronchospasm.
Maintenance Treatment of Asthma
SPIRIVA RESPIMAT 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: SPIRIVA RESPIMAT is NOT indicated for the relief of acute bronchospasm.
Dosage & Administration of Spiriva
Chronic Obstructive Pulmonary Disease
The recommended dosage for patients with COPD is 2 inhalations of SPIRIVA RESPIMAT 2.5 mcg per actuation once-daily; total dose equals 5 mcg of SPIRIVA RESPIMAT.
Asthma
The recommended dosage for patients with asthma is 2 inhalations of SPIRIVA RESPIMAT 1.25 mcg per actuation once-daily; total dose equals 2.5 mcg of SPIRIVA RESPIMAT. 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 .
Side Effects of Spiriva
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 . 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 Placebo *Adverse reactions include a grouping of similar terms Gastrointestinal Disorders Dry mouth 134 52 Infections and Infestations Pharyngitis 378 333 Respiratory, Thoracic, and Mediastinal Disorders Cough 190 182 Sinusitis 103 88 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.
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 Placebo *Adverse reactions include a grouping of similar terms Respiratory, Thoracic, and Mediastinal Disorders Pharyngitis 125 91 Sinusitis 21 10 Bronchitis 26 10 Nervous System Disorders Headache 30 20 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.
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.
Warnings & Cautions for Spiriva
Not for Acute Use
SPIRIVA RESPIMAT 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 beta 2 -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 SPIRIVA RESPIMAT. If such a reaction occurs, therapy with SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT.
Paradoxical Bronchospasm Inhaled medicines, including
SPIRIVA RESPIMAT, 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 SPIRIVA RESPIMAT should be stopped and other treatments considered.
Worsening of Narrow-Angle Glaucoma
SPIRIVA RESPIMAT 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
SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT should be monitored closely for anticholinergic side effects .
Drug Interactions with Spiriva
Concomitant Respiratory Medications
SPIRIVA RESPIMAT has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leukotriene modifiers, cromones, and anti-IgE treatment without increases in adverse reactions.
Anticholinergics
There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of SPIRIVA RESPIMAT with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.
Pregnancy Safety for Spiriva
Pregnancy Risk Summary The limited human data with SPIRIVA RESPIMAT 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 (see Clinical Considerations ). 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 (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 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/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 Spiriva
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 Flow Rates and Holding Times Using the Dose 2.5 mcg (as two actuations) Flow Rate (L/min) and corresponding age Mask Holding Time (seconds) Mean Medication Delivery through AeroChamber Plus Flow-Vu ® per Dose (mcg) Body Weight 50 th Percentile (kg) a Medication Delivered per Dose (ng/kg) b a Centers for Disease Control and Prevention growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion. Body weight values correspond to the average of the 50 percentile weight for boys and girls at the ages indicated. b Inhalation of SPIRIVA RESPIMAT 2.5 mcg dose (as two actuations) in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 2.5 mcg, or 36 ng/kg. 4.9 (6 to 12 Months) small 0 2 5 10 0.85 0.86 0.55 0.62 7.5-9.9 86-113 87-115 56-73 63-83 8.0 (2 to 5 Years) medium 0 2 5 10 0.74 0.93 0.72 0.57 12.3-18.0 41-60 52-76 40-59 32-46 12.0 (> 5 Years) medium 0 2 5 10 1.16 0.96 0.78 0.61 18.0 64 53 43 34 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 SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT delivered without a holding chamber typically represents approximately 60% of the delivered dose.
Contraindications for Spiriva
is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any component of this product . In clinical trials with SPIRIVA RESPIMAT, 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 component of this product.
Overdosage Information for Spiriva
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 manner, following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects.
Treatment of overdosage consists of discontinuation of SPIRIVA RESPIMAT together with institution of appropriate symptomatic and/or supportive therapy.
Clinical Studies of Spiriva
Chronic Obstructive Pulmonary Disease
The efficacy of SPIRIVA RESPIMAT compared to placebo was evaluated in 6 clinical trials: one dose-ranging trial and 5 confirmatory trials (Trials 1-5). In addition, SPIRIVA RESPIMAT was compared to SPIRIVA HandiHaler in a long-term active-controlled trial in COPD (Trial 6). Dose-Ranging Trial Dose selection for the Phase III clinical program was supported by a 3-week randomized, double-blind, placebo and active-controlled, parallel group trial in 202 COPD patients. A total of five doses of tiotropium RESPIMAT (1.25 to 20 mcg) were evaluated compared to placebo. Results demonstrated numerical improvements in FEV 1 at all doses compared to placebo.
The difference in trough FEV 1 from placebo for the 1.25, 2.5, 5, 10 and 20 mcg once daily doses were 0.08 L (95% CI -0.03, 0.20), 0.03 L (-0.08, 0.15), 0.13 L, 0.11 L (-0.004, 0.224), and 0.13 L, respectively. Based on these results, the 5 and 10 mcg doses were further evaluated in the confirmatory COPD trials. Confirmatory Trials A total of 6,614 COPD patients (2,801 receiving SPIRIVA RESPIMAT 5 mcg and 2,798 receiving placebo) were studied in the five confirmatory trials of SPIRIVA RESPIMAT. Trials 1 and 2 were 12-week, randomized, double-blind, placebo- and active- (ipratropium) controlled trials that evaluated bronchodilation.
Trials 3-5 were 48-week, randomized, double-blind, placebo-controlled, trials that evaluated bronchodilation and effects on COPD exacerbations. Trials 1-4 included both the tiotropium RESPIMAT 5 mcg and 10 mcg doses, whereas Trial 5 included only the 5 mcg dose. These trials 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 an FEV 1 less than or equal to 60% of predicted and a ratio of FEV 1 /FVC of less than or equal to 0.7. All treatments were administered once-daily in the morning.
Change from baseline in trough FEV 1 was a primary endpoint in all trials. Trials 3-5 included COPD exacerbations as primary endpoints. Baseline patient characteristics were similar across the five individual confirmatory trials, except for race in Trial 5 in which there were more Asian patients (30%) compared to other trials (<1%). The mean age ranged from 62 to 66 years.
Most patients were male (64-78%), ex-smokers (57-65%) and Caucasian (69-99%). Mean pre-bronchodilator FEV 1 was between 1.03 and 1.26 L with a mean FEV 1 /FVC ratio of 42-50%. Except for LABAs and other inhaled anticholinergic agents, other pulmonary medications were allowed as concomitant therapy in Trials 1-4. LABA use was permitted in Trial 5. Effect on Lung Function SPIRIVA RESPIMAT 5 mcg demonstrated significant improvement in trough FEV 1 compared to placebo in all 5 confirmatory trials (Table 4). The change from baseline in trough FEV 1 over time from Trial 4 is depicted in Figure 1 and is representative of the other two 48-week trials. In Trials 3 and 4 patients treated with SPIRIVA RESPIMAT 5 mcg also used less rescue medication compared to patients on placebo. Table 4 Mean Change from Baseline in Trough FEV 1 (L) at End of Treatment Trial SPIRIVA RESPIMAT 5 mcg N Placebo N Trough FEV 1 (L) at End of Treatment Difference from placebo (95% CI) † at week 12 ‡ at week 48 Trial 1† 85 87 0.11 Trial 2† 90 84 0.13 Trial 3‡ 326 296 0.14 Trial 4‡ 324 307 0.11 Trial 5‡ 1,889 1,870 0.10 Figure 1 Trough FEV 1 Change from Baseline over 48 weeks (Trial 4), SPIRIVA RESPIMAT 5 mcg Figure 1 Exacerbations Trials 3, 4, and 5 also evaluated the effect of SPIRIVA RESPIMAT 5 mcg on COPD exacerbations.
For Trials 3 and 4, a pooled analysis of exacerbation rate per patient year was pre-specified as a primary endpoint, while the primary endpoint for Trial 5 was time to first exacerbation. Trial 5 also included exacerbation rate per patient year as a secondary endpoint. Exacerbations were defined as a complex of respiratory events/symptoms with a duration of ≥3 days with ≥2 of the following (increase of symptoms or new onset): shortness of breath/dyspnea/shallow, rapid breathing; sputum production (volume); occurrence of purulent sputum; cough; wheezing; chest tightness.
In the pooled analysis of Trials 3 and 4, SPIRIVA RESPIMAT 5 mcg significantly reduced the number of COPD exacerbations compared to placebo with 0.78 exacerbations/patient year versus 1.0 exacerbations/patient year, respectively, with a rate ratio of 0.78 (95% CI 0.67, 0.92). Time to first exacerbation was also delayed in SPIRIVA RESPIMAT 5 mcg patients. For Trial 5, in addition to the definition above, an exacerbation also had to result in a change in or requirement of treatment. In Trial 5, treatment with SPIRIVA RESPIMAT 5 mcg delayed the time to first COPD exacerbation compared to treatment with placebo.
Consistent with the pooled analysis of Trials 3 and 4, for Trial 5, exacerbation rate was also lower in SPIRIVA RESPIMAT 5 mcg compared to placebo. In Trial 5, SPIRIVA RESPIMAT 5 mcg also reduced the risk of COPD exacerbation-related hospitalization (HR = 0.73; 95% CI = 0.59, 0.90) compared to placebo. Long-term Active-Controlled Mortality Trial Survival In a pooled analysis of SPIRIVA RESPIMAT placebo-controlled clinical trials with complete vital status (mortality) follow-up, including the three 48-week trials (Trial 3, 4, and 5) and one 24-week placebo-controlled trial, 68 deaths (Incidence Rate 2.64 deaths per 100 patient years) were observed in the SPIRIVA RESPIMAT 5 mcg treatment group compared to 51 deaths (Incidence Rate 1.98 deaths per 100 patient years) in those treated with placebo.
In a 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial of tiotropium bromide inhalation powder (SPIRIVA HandiHaler) in 5,992 COPD patients a similar incidence rate of death had been observed between SPIRIVA HandiHaler and placebo treated groups. For clarification of the observed difference in fatal events, a long-term, randomized, double-blind, double dummy, active-controlled trial with an observation period up to 3 years was conducted to evaluate the risk of all-cause mortality associated with the use of SPIRIVA RESPIMAT compared to SPIRIVA HandiHaler (Trial 6). The objective of this trial was to rule out a relative excess mortality risk of 25% for SPIRIVA RESPIMAT versus SPIRIVA HandiHaler. The primary endpoints were all-cause mortality and time to first COPD exacerbation.
Trial 6 also included a lung function sub-study which measured trough FEV 1 measured every 24 weeks for 120 weeks (461 patients receiving SPIRIVA RESPIMAT 5 mcg, 445 patients receiving SPIRIVA HandiHaler). In Trial 6, 5,711 patients received SPIRIVA RESPIMAT 5 mcg and 5,694 patients received SPIRIVA HandiHaler. All patients were followed for vital status (mortality) at the end of the trial. At baseline, patient characteristics were balanced between the two treatment arms.
The mean age was 65 years and approximately 70% of subjects were male. Approximately, 82% of patients were Caucasian, 14% were Asian, and 2% were Black. Mean post-bronchodilator FEV 1 was 1.34 L with a mean FEV 1 /FVC ratio of 50%. The majority of patients were GOLD II or III (48% and 40%, respectively). The vital status was confirmed in 99.7% of patients.
The median exposure to treatment was 835 days for both treatment groups. All-cause mortality was similar between SPIRIVA RESPIMAT 5 mcg and SPIRIVA HandiHaler with an estimated hazard ratio of 0.96. Table 5 All-cause Mortality of SPIRIVA RESPIMAT vs SPIRIVA HandiHaler (Trial 6) SPIRIVA RESPIMAT 5 mcg (N = 5,711) SPIRIVA HandiHaler (N = 5,694) a Hazard ratios were estimated from a Cox proportional hazard model. Number (%) of Deaths 423 439 Incidence Rate per 100 patient years 3.22 3.36 HR (95% CI) a 0.96 Cause of death was adjudicated by a blinded, independent committee.
Cardiovascular deaths included cardiac death, sudden cardiac death, and sudden death; as well as fatal events caused by a cardiac disorder, vascular disorder, or stroke. There were 113 patients (2%) treated with SPIRIVA RESPIMAT 5 mcg who had cardiovascular deaths compared to 101 (2%) patients treated with SPIRIVA HandiHaler. Of the cardiovascular deaths, 11 (0.2%) and 3 (0.1%) deaths were due to myocardial infarction in SPIRIVA RESPIMAT 5 mcg patients and SPIRIVA HandiHaler patients, respectively.
For cardiac deaths, sudden cardiac death, and sudden death, there were a total of 69 (1.2%) and 68 (1.2%) deaths in SPIRIVA RESPIMAT 5 mcg patients and SPIRIVA HandiHaler patients, respectively. Effect on Lung Function and Exacerbations In the lung function sub-study the effect of SPIRIVA RESPIMAT 5 mcg on trough FEV 1 over 120 weeks was similar to SPIRIVA HandiHaler with a mean difference of -0.010 L (95% CI -0.038 to 0.018 L). Trial 6 also included time to first exacerbation as a co-primary endpoint (exacerbations defined as in Trials 3-5). SPIRIVA RESPIMAT 5 mcg failed to demonstrate superiority to SPIRIVA HandiHaler with a similar time to first COPD exacerbation between treatment groups.
Asthma
The SPIRIVA RESPIMAT clinical development program included six 4-week to 8-week cross-over design trials and ten 12-week to 48-week parallel-arm design trials in adult, adolescent (aged 12 to 17 years) and pediatric (aged 1 to 11 years) patients with asthma symptomatic on at least ICS. In all trials, SPIRIVA RESPIMAT was administered on a background of ICS therapy. Dose Selection Dose selection for the confirmatory trials was based on three randomized, double-blind, placebo-controlled, 4-week to 8-week, cross-over trials in 256 adult patients, 105 adolescent (age 12 to 17 years) patients, and 101 pediatric (age 6 to 11 years) patients that assessed doses ranging from 1.25 mcg to 10 mcg once daily. Results demonstrated numerical improvements in FEV 1 at all doses compared to placebo; however, across the trials, the response was not dose-ordered.
For adult patients, in the 4-week trial the difference in peak FEV 1 within 3 h post-dosing (peak FEV 1, 0-3hr ) from placebo for the tiotropium RESPIMAT 1.25, 2.5, and 5 mcg doses were 0.138 L (95% CI 0.090, 0.186), 0.128 L, and 0.188 L, respectively. For adolescent patients, the difference in peak FEV 1, 0-3hr from placebo for the tiotropium RESPIMAT 1.25, 2.5, and 5 mcg doses were 0.067 L (95% CI −0.005, 0.138), 0.057 L (−0.021, 0.135), and 0.113 L, respectively. For pediatric patients, the difference in peak FEV 1, 0-3h from placebo for the tiotropium RESPIMAT 1.25, 2.5, and 5 mcg doses were 0.075 L (95% CI, 0.030, 0.120), 0.104 L, and 0.087 L, respectively.
The 10 mcg dose offered no substantial benefit over lower doses and resulted in more systemic anticholinergic side effects (e.g., dry mouth). The two dose regimen trials in adults with asthma were randomized, double-blind, 4-week, cross-over trials comparing tiotropium RESPIMAT 2.5 mcg twice-daily with 5 mcg once-daily. 24-hour FEV 1 results demonstrated comparable treatment effects for twice-daily and once-daily dosing. 12-week to 48-week Parallel-Arm Design Trials in Adults The program for persistent asthma in adult patients included one 12-week (Trial 1), two replicate 24-week (Trials 2 and 3), and two replicate 48-week (Trials 4 and 5) randomized, double-blind, placebo-controlled trials in a total of 3,476 asthma patients (673 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 1,128 receiving SPIRIVA RESPIMAT 5 mcg once-daily, 541 receiving salmeterol 50 mcg twice daily, and 1,134 receiving placebo) on background treatment of at least ICS. Trial 1 evaluated three treatments: SPIRIVA RESPIMAT 2.5 mcg once-daily, SPIRIVA RESPIMAT 5 mcg once-daily, and placebo. Trials 2 and 3 evaluated four treatments: SPIRIVA RESPIMAT 2.5 mcg once-daily, SPIRIVA RESPIMAT 5 mcg once-daily, salmeterol 50 mcg twice daily, and placebo. Trials 4 and 5 evaluated two treatments: SPIRIVA RESPIMAT 5 mcg once-daily and placebo.
All trials enrolled patients who had a diagnosis of asthma, were 18 to 75 years of age, and were not current smokers. Patients enrolled in Trials 4 and 5 were required to have airway obstruction that was not fully reversible (post-bronchodilator FEV 1 /FVC, 0.70). The majority of the 3,476 patients in the adult asthma trials were female (60%), Caucasian (61%) or Asian (31%), and had never smoked (81%) with a mean age of 46 years. The patient characteristics for the 12 week to 48 week trials in adult patients with asthma are summarized in Table 6. Table 6 Summary of Baseline Patient Characteristics, Adult Confirmatory Studies Adults, 18 yrs and older Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 Demographics Mean age in years (range) 42.9 (18 – 74) 43.3 (18 – 75) 42.9 (18 – 75) 53.4 (18-75) 52.5 (19-75) Mean duration of asthma (years) 16.2 21.7 21.8 31.5
Smoking status, ex-smoker (%) 18 14 19 22 26 Laboratory (median) Absolute
eosinophils (10 9 /L) 0.33 0.36 0.35 0.35 0.38 Total IgE (microgram/L) 536 638 641 601 449 Pulmonary function test (mean) Pre-bronchodilator FEV 1 (L) 2.30 2.18 2.21 1.55 1.59 Reversibility (%) 24.8 22.8 22.0 15.4
Absolute reversibility (mL) 556 488 477 215 218 Post-bronchodilator
FEV 1 /FVC (%) 74 72 72 60 59 The primary efficacy endpoint in Trial 1 was change from pre-treatment baseline in peak FEV 1, 0-3hr at week 12. The co-primary efficacy endpoints in Trials 2 and 3 were change from pre-treatment baseline in peak FEV 1, 0-3hr and change from pre-treatment baseline in trough FEV 1 at week 24. Additional efficacy measures included asthma exacerbation, Asthma Control Questionnaire (ACQ), and Asthma Quality of Life Questionnaire (AQLQ). For Trials 1, 2, and 3, SPIRIVA RESPIMAT 2.5 mcg showed statistically significant improvements in lung function over placebo when used in addition to background treatment of ICS (Table 7). Table 7 Differences from Placebo in Peak FEV 1, 0-3 hr and Trough FEV 1, Adult Confirmatory Studies at Primary Endpoint Time Evaluation Treatment (Duration) ICS Background Treatment b,c Treatment in mcg/day n Peak FEV 1, 0-3hr, in L a Trough FEV 1, in L a Δ from baseline Difference from placebo Δ from baseline Difference from placebo Mean 95% CI Mean 95% CI a Means adjusted for treatment, center/country, visit, visit*treatment, baseline, baseline*visit. b Additional asthma medications allowed in stable doses prior to and throughout the trials. c Low dose ICS = 200–400 mcg budesonide-equivalent. Medium dose ICS = 400–800 mcg budesonide-equivalent. Adult patients, age 18 years and older Trial 1 (12 weeks) Low dose ICS SPIRIVA RESPIMAT 2.5 mcg Placebo 154 155 0.29 0.13 0.16 0.09, 0.23 0.13 0.02 0.11 0.04, 0.18 Trial 2 (24 weeks) Medium dose ICS SPIRIVA RESPIMAT 2.5 mcg Salmeterol 100 mcg Placebo 259 271 265 0.29 0.27 0.05 0.24 0.21 0.18, 0.29 0.16, 0.27 0.15 0.09 −0.03 0.19 0.12 0.13, 0.24 0.06, 0.18 Trial 3 (24 weeks) Medium dose ICS SPIRIVA RESPIMAT 2.5 mcg Salmeterol 100 mcg Placebo 256 264 253 0.29 0.25 0.08 0.21 0.18 0.16, 0.26 0.12, 0.23 0.16 0.09 −0.01 0.18 0.11 0.12, 0.23 0.05, 0.16 Trials 1, 2, and 3 also included a SPIRIVA RESPIMAT 5 mcg once daily treatment arm.
In these asthma trials, the FEV 1 response (change from baseline for tiotropium compared to placebo) was generally lower for the 5 mcg dose compared to the 2.5 mcg dose. The peak FEV 1 0-3hr response was 16% to 20% lower for the 5 mcg dose compared to the 2.5 mcg dose in all three trials, and, the trough FEV 1 response was 11% higher for the 5 mcg dose compared to the 2.5 mcg dose for one trial (Trial 1) and 18% and 24% lower for the 5 mcg dose compared to the 2.5 mcg dose for the other two trials (Trials 2 and 3). Improvements in morning and evening peak expiratory flow (PEF) were consistent with the observed FEV 1 treatment response. Examination of age, gender, smoking history, and serum IgE level subgroups did not identify differences in response among these subgroups.
The improvement of lung function compared to placebo was maintained for 24 hours (Figure 2). The bronchodilator effects of SPIRIVA RESPIMAT 2.5 mcg were apparent after first dose; however, maximum bronchodilator effect took up to 4 to 8 weeks to be achieved. Figure 2 FEV 1 Response over 24-Hours following 24-Weeks of Treatment, Trial 3 Asthma exacerbation was assessed in Trials 2 and 3 over the 24-week treatment periods. An asthma exacerbation was defined as an episode of progressive increase in ≥1 asthma symptom(s), such as shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms or a decrease of a patient's best morning PEF of 30% from a patient's mean morning PEF for ≥2 consecutive days that required the initiation or increase in treatment with systemic steroids for ≥3 days.
Results of asthma exacerbation are shown in Table 8. Table 8 Exacerbations in Patients on ICS over 24-Weeks Trial 2 Trial 3 SPIRIVA RESPIMAT 2.5 mcg (N=259) Placebo (N=265) SPIRIVA RESPIMAT 2.5 mcg (N=256) Placebo (N=253) Number of patients with at least 1 event, n (%) 9 24 13 19 Rate of exacerbations per patient year Mean rate of events 0.08 0.24 0.13 0.18 Comparison to Placebo, Rate ratio (95% CI) 0.32 0.70 Time to first asthma exacerbation Comparison to Placebo, Hazard ratio (95% CI) 0.37 0.66 Trials 2 and 3 also evaluated the rate of exacerbations and time to first asthma exacerbation for the SPIRIVA RESPIMAT 5 mcg dose. The rate of asthma exacerbations compared to placebo for SPIRIVA RESPIMAT 5 mcg was 0.78 (95% CI 0.55, 1.10) in Trial 2 and 0.76 in Trial 3. The hazard ratio for time to first asthma exacerbation for SPIRIVA RESPIMAT 5 mcg compared to placebo was 0.72 (95% CI 0.39, 1.35), in Trial 2 and 0.72 in Trial 3. ACQ and AQLQ were assessed in Trials 2 and 3 at week 24. In Trial 2, the ACQ-7 (7 items) responder rate (defined as a change in score ≥0.5) for the SPIRIVA RESPIMAT 2.5 mcg treatment arm was 63% compared to 53% for placebo with an odds ratio of 1.47 (95% CI 1.02, 2.11). The ACQ-5 (derived from ACQ 7 by removing the FEV 1 component and rescue bronchodilator component) results also had a similar trend. In Trial 2, the AQLQ responder rate (defined as a change in score ≥0.5) for the SPIRIVA RESPIMAT 2.5 mcg treatment arm was 58% compared to 50% for placebo with an odds ratio of 1.34 (95% CI 0.94, 1.93). 12-week and 48-week Parallel-Arm Design Trials in Adolescents 12-17 Years of Age Efficacy in adolescents was based on partial extrapolation of efficacy in adults and two randomized, double-blind, placebo-controlled trials of 12 and 48 weeks duration in a total of 789 asthma patients 12 to 17 years of age (252 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 264 receiving 5 mcg once-daily, and 273 receiving placebo). The 12-week trial enrolled patients with severe asthma who were on background treatment of ICS plus one or more controller medications (e.g.
LABA). The 48-week trial enrolled patients with moderate asthma on background treatment of at least ICS. The majority of the patients in the trials were male (63.4%), Caucasian (93.7%) and had never smoked (99.9%) with a mean age of 14.3 years. The primary efficacy endpoint in both trials was change from pre-treatment baseline in peak FEV 1, 0-3hr. The primary endpoint evaluation for FEV 1 was defined at week 24 for the 48-week trial and at end of the treatment period (week 12) for the 12-week trial.
Given the demonstration of efficacy in the adult population, the results of the 2 trials support the efficacy of SPIRIVA RESPIMAT 2.5 mcg once daily in adolescent patients 12-17 years of age with asthma (mean difference in peak FEV 1, 0-3hr from placebo for SPIRIVA RESPIMAT 2.5 mcg were 0.13 L (95% CI 0.03, 0.23) and 0.11 L for the 48-week and 12-week trials, respectively). 12-week and 48-week Parallel-Arm Design Trials in Pediatric Patients 6-11 Years of Age Efficacy in pediatric patients 6-11 years of age was based on partial extrapolation of efficacy in adults and two randomized, double-blind, placebo-controlled trials of 12 and 48 weeks duration in a total of 801 asthma patients 6 to 11 years of age (271 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 265 receiving 5 mcg once-daily, and 265 receiving placebo). The 12-week trial enrolled patients with severe asthma who were on background treatment of ICS plus one or more controller medications (e.g. LABA). The 48-week trial enrolled patients with moderate asthma on background treatment of at least ICS. The primary efficacy endpoint in both trials was change from pre-treatment baseline in peak FEV 1, 0-3hr with the evaluation defined at week 24 for the 48-week trial and at end of the treatment period (week 12) for the 12-week trial. The majority of the patients in the trials were male (67.8%) and Caucasian (87.0%) with a mean age of 9.0 years.
Compared to placebo, SPIRIVA RESPIMAT 2.5 mcg once daily had a significant effect on the primary endpoint in the 48 week, but not the 12 week trial, with mean differences in peak FEV 1, 0-3hr from placebo of 0.17 L (95% CI 0.11, 0.23) and 0.04 L (95% CI -0.03, 0.10) for the 48-week and 12-week trials, respectively. Given the demonstration of efficacy in the adult and adolescent population, the results support the efficacy of SPIRIVA RESPIMAT 2.5 mcg once daily in pediatric patients 6-11 years of age with asthma. Figure 2
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.
Ready to save on Spiriva?
Compare prescription prices at over 70,000 pharmacies and start saving today—no enrollment required.
Compare Spiriva Prices