The following Structured Product Label (SPL) was submitted to the FDA by Boehringer Ingelheim Pharmaceuticals, Inc. for the product Spiriva Respimat (NDC 0597-0100). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1.1 maintenance treatment of chronic obstructive pulmonary disease, 1.2 maintenance treatment of asthma, 2 dosage and administration, 2.1 chronic obstructive pulmonary disease, 2.2 asthma, 2.3 special populations, 3 dosage forms and strengths, 4 contraindications, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
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.
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.
To receive the full dose of medication, SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT 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 [see Patient Counseling Information (17)].
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.
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 [see Patient Counseling Information (17)].
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 [see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)].
SPIRIVA RESPIMAT consists of a SPIRIVA RESPIMAT inhaler and an aluminum cylinder (SPIRIVA RESPIMAT cartridge) containing tiotropium bromide (as the monohydrate). The SPIRIVA RESPIMAT cartridge is only intended for use with the SPIRIVA RESPIMAT inhaler.
SPIRIVA RESPIMAT is available in two dosage strengths. Each actuation from the SPIRIVA RESPIMAT inhaler delivers 1.25 mcg or 2.5 mcg of tiotropium (equivalent to 1.562 mcg or 3.124 mcg, respectively, of tiotropium bromide monohydrate) from the mouthpiece. Two actuations equal one dose (2.5 mcg or 5 mcg).
SPIRIVA RESPIMAT is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any component of this product [see Warnings and Precautions (5.2)]. 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 [see Warnings and Precautions (5.2)].
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 beta2-agonist should be used.
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.
Inhaled medicines, including SPIRIVA RESPIMAT, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-acting beta2-agonist such as albuterol. Treatment with SPIRIVA RESPIMAT should be stopped and other treatments considered.
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.
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.
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 [see Clinical Pharmacology (12.3)].
The following adverse reactions are described, or described in greater detail, in other sections:
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 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 6565 adult COPD patients (75% males and 25% females) 40 years of age and older. Of these patients, 3282 patients were treated with SPIRIVA RESPIMAT 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 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.
| *Adverse reactions include a grouping of similar terms | ||
| Body System (Reaction)* | SPIRIVA RESPIMAT
5 mcg [n=3282] | Placebo [n=3283] |
| 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.
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 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
SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT 2.5 mcg treatment group, and a higher incidence rate on SPIRIVA RESPIMAT 2.5 mcg than on placebo.
| *Adverse reactions include a grouping of similar terms | |||
| Body System (Reaction)* | SPIRIVA RESPIMAT
2.5 mcg [n=787] | Placebo [n=735] | |
| 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 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
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 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.
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 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 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.
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.
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.
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 [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].
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/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).
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 [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SPIRIVA RESPIMAT and any potential adverse effects on the breastfed child from SPIRIVA RESPIMAT 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.
The safety and efficacy of SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT 2.5 mcg; in three additional clinical trials, 345 patients aged 6 to 11 years with asthma were treated with SPIRIVA RESPIMAT 2.5 mcg. Patients in these age groups demonstrated efficacy results similar to those observed in patients aged 18 years and older with asthma [see Clinical Studies (14.2)].
The safety and efficacy of SPIRIVA RESPIMAT have not been established in pediatric patients less than 6 years of age. The safety of SPIRIVA RESPIMAT 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, SPIRIVA RESPIMAT 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 [See Adverse Reactions (6.2)].
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.
| a Centers for Disease Control
growth charts, developed by the National Center for Health Statistics
in collaboration with the National Center for Chronic Disease Prevention
and Health Promotion (2009). 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. | |||||
| Flow Rate (L/min) and corresponding age | Mask | Holding Time (seconds) | Mean Medication Delivery through AeroChamber Plus Flow-Vu® per Dose (mcg) | Body Weight 50th Percentile (kg)a | Medication Delivered per Dose (ng/kg)b |
| 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.
Based on available data, no adjustment of SPIRIVA RESPIMAT dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].
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 SPIRIVA RESPIMAT 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.
The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.
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 SPIRIVA RESPIMAT together with institution of appropriate symptomatic and/or supportive therapy.
The active component of SPIRIVA RESPIMAT is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol.
The structural formula is:
Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O.
The drug product, SPIRIVA RESPIMAT, is composed of a sterile, aqueous solution of tiotropium bromide filled into a 4.5 mL plastic container crimped into an aluminum cylinder (SPIRIVA RESPIMAT cartridge) for use with the SPIRIVA RESPIMAT inhaler. Excipients include water for injection, edetate disodium, benzalkonium chloride and hydrochloric acid. The SPIRIVA RESPIMAT cartridge is only intended for use with the SPIRIVA RESPIMAT inhaler. The RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow moving aerosol cloud of medication from a metered volume of the drug solution.
When used with the SPIRIVA RESPIMAT inhaler, each cartridge containing 4 grams of sterile aqueous solution delivers the labeled number of metered actuations after preparation for use. Each dose (one dose equals two actuations) from the SPIRIVA RESPIMAT inhaler delivers 2.5 mcg or 5 mcg of tiotropium in 22.1 mcL from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).
Prior to first use, the SPIRIVA RESPIMAT cartridge is inserted into the SPIRIVA RESPIMAT 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 [see Patient Counseling Information (17)].
Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.
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.
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 SPIRIVA RESPIMAT 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.
Specific Populations
Geriatric Patients
As expected
for all predominantly renally excreted drugs, advancing age was associated
with a decrease of tiotropium renal clearance (347 mL/min in COPD
patients <65 years to 275 mL/min in COPD patients ≥65 years).
This did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values following inhalation of
the solution. Exposure to tiotropium was not found to differ with
age in patients with asthma.
Pediatric Patients
The peak and total exposure to tiotropium was not found to differ
between pediatric patients (aged 6 to 17 years) and adults with asthma.
Renal Impairment
Following 4-week SPIRIVA RESPIMAT 5 mcg once daily dosing
in patients with COPD, mild renal impairment (creatinine clearance
60 - <90 mL/min) resulted in 23% higher AUC0‑6,ss and 17% higher Cmax,ss values; moderate renal
impairment (creatinine clearance 30 - <60 mL/min) resulted in 57%
higher AUC0‑6,ss and 31% higher Cmax,ss values compared to COPD patients with normal renal
function (creatinine clearance >90 mL/min).
The influence of mild or moderate renal impairment on the systemic
exposure to SPIRIVA RESPIMAT 2.5 mcg in patients with asthma was similar
to what has been described for COPD above. There lacks sufficient
data of tiotropium exposure in patients with severe renal impairment
(creatinine clearance <30 mL/min) following inhalation of SPIRIVA
RESPIMAT. However AUC0-4 and Cmax were 94% and 52% higher, respectively, in patients with severe renal
impairment following intravenous infusion of tiotropium bromide.
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics
of tiotropium were not studied.
Drug Interactions
An interaction study with tiotropium (14.4 mcg intravenous infusion
over 15 minutes) and cimetidine 400 mg three times daily or ranitidine
300 mg once-daily was conducted. Concomitant administration of cimetidine
with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and no significant
change in the Cmax and amount excreted in urine
over 96 hours. Co-administration of tiotropium with ranitidine did
not affect the pharmacokinetics of tiotropium.
Common concomitant medications (LABA, ICS) used by patients with COPD were not found to alter the exposure to tiotropium. Similarly, common concomitant medications (LABA, ICS+LABA combinations, oral corticosteroids and leukotriene modifiers) used by patients with asthma were not found to alter the exposure to tiotropium.
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).
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 FEV1 at all doses compared to placebo. The difference in trough FEV1 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 (0.02, 0.25), 0.11 L (-0.004, 0.224), and 0.13 L (0.01, 0.24),
respectively. Based on these results, the 5 and 10 mcg doses were
further evaluated in the confirmatory COPD trials.
Confirmatory Trials
A total of 6614 COPD patients (2801 receiving SPIRIVA
RESPIMAT 5 mcg and 2798 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 FEV1 less than or
equal to 60% of predicted and a ratio of FEV1/FVC of less than or equal to 0.7. All treatments were administered
once-daily in the morning. Change from baseline in trough FEV1 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 FEV1 was between 1.03 and 1.26 L with a mean FEV1/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
FEV1 compared to placebo in all 5 confirmatory
trials (Table 4). The change from baseline in trough FEV1 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.
| † at week 12 | |||
| ‡ at week 48 | |||
| Trial | SPIRIVA RESPIMAT 5 mcg N | Placebo N | Trough FEV1 (L) at End of Treatment Difference from placebo (95% CI) |
| Trial 1† | 85 | 87 | 0.11 (0.04, 0.18) |
| Trial 2† | 90 | 84 | 0.13 (0.07, 0.18) |
| Trial 3‡ | 326 | 296 | 0.14 (0.10, 0.18) |
| Trial 4‡ | 324 | 307 | 0.11 (0.08, 0.15) |
| Trial 5‡ | 1889 | 1870 | 0.10 (0.09, 0.12) |
Figure 1 Trough FEV1 Change from Baseline over 48 weeks (Trial 4), SPIRIVA RESPIMAT 5 mcg
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 [hazard ratio of 0.69 (95% CI 0.63, 0.77)]. 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 5992 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 FEV1 measured every 24 weeks for 120 weeks (461 patients receiving SPIRIVA RESPIMAT 5 mcg, 445 patients receiving SPIRIVA HandiHaler).
In Trial 6, 5711 patients received SPIRIVA RESPIMAT 5 mcg and 5694 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 FEV1 was 1.34 L with a mean FEV1/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 [(95% CI of (0.84 to 1.09), Table 5].
| a Hazard ratios were estimated from a Cox proportional hazard model. | ||
| SPIRIVA RESPIMAT 5 mcg (N = 5711) | SPIRIVA HandiHaler (N = 5694) | |
| Number (%) of Deaths | 423 (7.4) | 439 (7.7) |
| Incidence Rate per 100 patient years | 3.22 | 3.36 |
| HR (95% CI)a | 0.96 (0.84, 1.09) | |
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 FEV1 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 [hazard ratio of 0.98 (95% CI 0.93 to 1.03)].
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 FEV1 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 FEV1 within 3 h post-dosing (peak FEV1, 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 (0.080, 0.176), and 0.188
L (0.140, 0.236), respectively. For adolescent patients, the difference
in peak FEV1, 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 (0.036, 0.190), respectively.
For pediatric patients, the difference in peak FEV1, 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 (0.059, 0.149), and
0.087 L (0.042, 0.132), 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 FEV1 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 3476 asthma patients (673 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily,
1128 receiving SPIRIVA RESPIMAT 5 mcg once-daily, 541 receiving salmeterol
50 mcg twice daily, and 1134 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
FEV1/FVC, 0.70). The majority of the 3476 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.
| 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 | 29.1 |
| Smoking status, ex-smoker (%) | 18 | 14 | 19 | 22 | 26 |
| Laboratory (median) | |||||
| Absolute eosinophils (109/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 FEV1 (L) | 2.30 | 2.18 | 2.21 | 1.55 | 1.59 |
| Reversibility (%) | 24.8 | 22.8 | 22.0 | 15.4 | 15.0 |
| Absolute reversibility (mL) | 556 | 488 | 477 | 215 | 218 |
| Post-bronchodilator FEV1/FVC (%) | 74 | 72 | 72 | 60 | 59 |
The primary efficacy endpoint in Trial 1 was change from pre-treatment baseline in peak FEV1, 0-3h at week 12. The co-primary efficacy endpoints in Trials 2 and 3 were change from pre-treatment baseline in peak FEV1, 0-3 hr and change from pre-treatment baseline in trough FEV1 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).
| 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. | ||||||||
| Treatment (Duration) ICS Background Treatment b,c | Treatment in mcg/day | n | Peak FEV1, 0- 3hr, in L a | Trough FEV1 , in L a | ||||
| Δ from baseline | Difference from placebo | Δ from baseline | Difference from placebo | |||||
| Mean | 95% CI | Mean | 95% CI | |||||
| 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 FEV1 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 FEV1, 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 FEV1 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 FEV1 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 FEV1 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.
| 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 (3.5) | 24 (9.1) | 13 (5.1) | 19 (7.5) |
| 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 (0.20, 0.51) | 0.70 (0.46, 1.08) | ||
| Time to first asthma exacerbation | ||||
Comparison to Placebo, Hazard ratio (95% CI) | 0.37 (0.17, 0.80) | 0.66 (0.33, 1.34) | ||
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 (0.50, 1.16) 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 (0.36, 1.43) 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 FEV1 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 FEV1, 0-3hr. The primary endpoint evaluation for FEV1 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 FEV1, 0-3hr from placebo for SPIRIVA RESPIMAT 2.5 mcg were 0.13 L (95% CI 0.03, 0.23) and 0.11 L (0.002, 0.22) 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 FEV1, 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 FEV1, 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.
SPIRIVA RESPIMAT Inhalation Spray is supplied in a carton containing one SPIRIVA RESPIMAT cartridge and one SPIRIVA RESPIMAT inhaler.
The SPIRIVA RESPIMAT cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap. The SPIRIVA RESPIMAT cartridge is only intended for use with the SPIRIVA RESPIMAT inhaler and should not be interchanged with any other RESPIMAT device delivered product.
The SPIRIVA RESPIMAT inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The written information on the label of the gray inhaler body indicates that it is labeled for use with the SPIRIVA RESPIMAT cartridge.
SPIRIVA RESPIMAT Inhalation Spray is available in two dosage strengths, identified by dose delivered per actuation and by the color of the cap and associated container label: aqua represents 2.5 mcg per actuation; blue represents 1.25 mcg per actuation.
To deliver the recommended dosage for COPD:
To deliver the recommended dosage for asthma:
The SPIRIVA RESPIMAT cartridge for each strength has a net fill weight of 4 grams and when used with the SPIRIVA RESPIMAT inhaler, is designed to deliver the labeled number of metered actuations after preparation for use. Each actuation from the SPIRIVA RESPIMAT inhaler delivers 1.25 or 2.5 mcg of tiotropium (equivalent to 1.562 or 3.124 mcg, respectively, of tiotropium bromide monohydrate) from the mouthpiece.
When the labeled number of actuations has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.
After assembly, the SPIRIVA RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.
Keep out of reach of children. Do not spray into eyes.
Storage
Store at 25°C (77°F); excursions
permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature]. Avoid freezing.
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Not for Acute Use
Instruct patients
that SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT. Advise
patient to immediately discontinue treatment and consult a physician
should any of these signs or symptoms develop.
Paradoxical Bronchospasm
Inform patients that SPIRIVA RESPIMAT can produce paradoxical
bronchospasm. Advise patients that if paradoxical bronchospasm occurs,
patients should discontinue SPIRIVA RESPIMAT.
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 SPIRIVA RESPIMAT, 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 SPIRIVA RESPIMAT treatment.
Instructions for Administering
SPIRIVA RESPIMAT
It is important for patients
to understand how to correctly administer SPIRIVA inhalation spray
using the SPIRIVA RESPIMAT inhaler. Instruct patients that SPIRIVA
inhalation spray should only be administered via the SPIRIVA RESPIMAT
inhaler and the SPIRIVA RESPIMAT inhaler should not be used for administering
other medications.
Instruct patients that priming SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT inhaler and the unit is primed. SPIRIVA RESPIMAT 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 SPIRIVA RESPIMAT should be used with an adult’s assistance.
Distributed by:
Boehringer Ingelheim
Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY.
SPIRIVA®, HANDIHALER®, and RESPIMAT® are registered trademarks and are used under license from Boehringer Ingelheim International GmbH
Copyright © 2017
Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
IT5904FB152017
Spiriva Respimat 1.25 mcg
Carton
Cartridge
Inhaler
Spiriva Respimat 1.25 mcg
Professional Sample
Carton
Cartridge
Inhaler
Spiriva Respimat 2.5 mcg
Carton
Cartridge
Inhaler
Spiriva Respimat 2.5 mcg
Professional Sample
Carton
Cartridge
Inhaler
* Please review the disclaimer below.
