Generic Name: tiotropium bromide
Dosage Form: inhalation powder, oral capsule
1 INDICATIONS AND USAGE
Spiriva HandiHaler (tiotropium bromide inhalation powder) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Spiriva HandiHaler is indicated to reduce exacerbations in COPD patients.
2 DOSAGE AND ADMINISTRATION
Spiriva capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of the Spiriva capsules are only for oral inhalation and should only be used with the HandiHaler device [see Overdosage (10)].
The recommended dose of Spiriva HandiHaler is two inhalations of the powder contents of one Spiriva capsule, once-daily, with the HandiHaler device [see Patient Counseling Information (17)].
For administration of Spiriva HandiHaler, a Spiriva capsule is placed into the center chamber of the HandiHaler device. The Spiriva capsule is pierced by pressing and releasing the green piercing button on the side of the HandiHaler device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece [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 HandiHaler 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)].
3 DOSAGE FORMS AND STRENGTHS
Spiriva HandiHaler consists of Spiriva capsules and a HandiHaler device. Spiriva capsules contain 18 mcg dry powder formulation of tiotropium in a light green, hard gelatin capsule with TI 01 printed on one side and Boehringer Ingelheim company logo on the other side.
Spiriva HandiHaler is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of Spiriva capsules [see WARNINGS AND PRECAUTIONS (5.2)]. In clinical trials and postmarketing experience with Spiriva HandiHaler, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported.
5 WARNINGS AND PRECAUTIONS
Not for Acute Use
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 HandiHaler. If such a reaction occurs, therapy with Spiriva HandiHaler should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to Spiriva HandiHaler. In addition, Spiriva HandiHaler should be used with caution in patients with severe hypersensitivity to milk proteins.
Worsening of Narrow-Angle Glaucoma
Spiriva HandiHaler should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
Worsening of Urinary Retention
Spiriva HandiHaler should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). 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 ≤50 mL/min) treated with Spiriva HandiHaler should be monitored closely for anticholinergic side effects [see Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
- Immediate hypersensitivity reactions [see Warnings and Precautions (5.2)]
- Paradoxical bronchospasm [see Warnings and Precautions (5.3)]
- Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)]
- Worsening of urinary retention [see Warnings and Precautions (5.5)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to Spiriva HandiHaler in 2663 patients. Spiriva HandiHaler was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with Spiriva HandiHaler at the recommended dose of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database because only serious adverse events were collected.
The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention.
Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated Spiriva HandiHaler in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the Spiriva HandiHaler group in the 1-year placebo-controlled trials where the rates in the Spiriva HandiHaler group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison.
|Body System (Event)||Placebo-Controlled Trials||Ipratropium-Controlled Trials|
(n = 550)
(n = 371)
(n = 356)
(n = 179)
|Body as a Whole
Chest Pain (non-specific)
|Gastrointestinal System Disorders
|Resistance Mechanism Disorders
|Respiratory System (Upper)
Upper Respiratory Tract Infection
|Skin and Appendage Disorders
Urinary Tract Infection
Other reactions that occurred in the Spiriva HandiHaler group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention.
In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age [see Use in Specific Populations (8.5)].
Two multicenter, 6-month, controlled studies evaluated Spiriva HandiHaler in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials.
The data described below reflect exposure to Spiriva HandiHaler in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2986 patients were treated with Spiriva HandiHaler at the recommended dose of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. When the adverse reactions were analyzed with a frequency of ≥3% in the Spiriva HandiHaler group where the rates in the Spiriva HandiHaler group exceeded placebo by ≥1%, adverse reactions included (Spiriva HandiHaler, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%).
Additional Adverse Reactions
Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with Spiriva HandiHaler than placebo include: dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling.
Adverse reactions have been identified during worldwide post-approval use of Spiriva HandiHaler. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are: application site irritation (glossitis, mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria.
7 DRUG INTERACTIONS
Sympathomimetics, Methylxanthines, Steroids
Spiriva HandiHaler has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse drug reactions.
There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of Spiriva HandiHaler 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)].
No clinically significant interaction occurred between tiotropium and cimetidine or ranitidine [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
Teratogenic Effects, Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Spiriva HandiHaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
No evidence of structural alterations was observed in rats and rabbits at inhalation tiotropium doses of up to approximately 660 and 6 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at inhalation tiotropium doses of approximately 35 times the RHDID on a mg/m2 basis. In rabbits, tiotropium caused an increase in post-implantation loss at an inhalation dose of approximately 360 times the RHDID on a mg/m2 basis. Such effects were not observed at inhalation doses of approximately 4 and 80 times the RHDID on a mg/m2 basis in rats and rabbits, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
Labor and Delivery
Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if Spiriva HandiHaler is administered to a nursing woman.
Spiriva HandiHaler is approved for use in the maintenance treatment of bronchospasm associated with COPD and for the reduction of COPD exacerbations. COPD does not normally occur in children. The safety and effectiveness of Spiriva HandiHaler in pediatric patients have not been established.
Of the total number of patients who received Spiriva HandiHaler in the 1-year clinical trials, 426 were <65 years, 375 were 65 to 74 years, and 105 were ≥75 years of age. Within each age subgroup, there were no differences between the proportion of patients with adverse events in the Spiriva HandiHaler and the comparator groups for most events. Dry mouth increased with age in the Spiriva HandiHaler group (differences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A higher frequency of constipation and urinary tract infections with increasing age was observed in the Spiriva HandiHaler group in the placebo-controlled studies. The differences from placebo for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these groups. Based on available data, no adjustment of Spiriva HandiHaler dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].
Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Spiriva HandiHaler should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].
High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium.
A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, Spiriva HandiHaler was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day.
No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7300, 120,000, and 850 times the recommended human daily inhalation dose on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
Each light green, hard gelatin Spiriva capsule contains 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins) as the carrier.
The active component of Spiriva HandiHaler is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2β, 4β, 5α, 7β)-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 HandiHaler device is an inhalation device used to inhale the dry powder contained in the Spiriva capsule. The dry powder is delivered from the HandiHaler device at flow rates as low as 20 L/min. Under standardized in vitro testing, the HandiHaler device delivers a mean of 10.4 mcg tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function [mean FEV1 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) through the HandiHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the HandiHaler device, which may vary from patient to patient, and may vary with the exposure time of the Spiriva capsule outside the blister pack.
12 CLINICAL PHARMACOLOGY
Mechanism of Action
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.
In a multicenter, randomized, double-blind trial 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 HandiHaler group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of >500 msec. Other clinical studies with Spiriva HandiHaler did not detect an effect of the drug on QTc intervals.
The effect of Spiriva HandiHaler on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received Spiriva HandiHaler 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 Spiriva HandiHaler 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 by dry powder inhalation. In common with other inhaled drugs, the majority of the delivered dose is deposited in the gastrointestinal tract and, to a lesser extent, in the lung, the intended organ. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.
Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. It is expected from the chemical structure of the compound (quaternary ammonium compound) that tiotropium is poorly absorbed from the gastrointestinal tract. The effect of food on tiotropium's bioavailability has not been studied. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Maximum tiotropium plasma concentrations were observed 5 minutes after inhalation.
Tiotropium shows a volume of distribution of 32 L/kg indicating that the drug binds extensively to tissues. The human plasma protein binding for tiotropium is 72%. At steady state, peak tiotropium plasma levels in COPD patients were 17 to 19 pg/mL when measured 5 minutes after dry powder inhalation of an 18 mcg dose and decreased in a multi-compartmental manner. Steady-state trough plasma concentrations were 3 to 4 pg/mL. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not readily penetrate the blood-brain barrier.
The extent of metabolism appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors.
In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.
The terminal elimination half-life of tiotropium was between 5 and 6 days following inhalation. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an inter-individual variability of 22%. Intravenously administered tiotropium was mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed drug in the gut which was eliminated via the feces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating active secretion into the urine. After chronic once-daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2 to 3 weeks with no accumulation thereafter.
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.
As expected for drugs predominantly excreted renally, advanced age was associated with a decrease of tiotropium renal clearance (326 mL/min in COPD patients <58 years to 163 mL/min in COPD patients >70 years), which may be explained by decreased renal function. Tiotropium excretion in urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients). Plasma concentrations were numerically increased with advancing age within COPD patients (43% increase in AUC0-4 after dry powder inhalation), which was not significant when considered in relation to inter- and intra-individual variability [see Dosage and Administration (2) and Use in Specific Populations (8.5)].
Since tiotropium is predominantly renally excreted, renal impairment was associated with increased plasma drug concentrations and reduced drug clearance after both intravenous infusion and dry powder inhalation. Mild renal impairment (creatinine clearance of 50 to 80 mL/min), which is often seen in elderly patients, increased tiotropium plasma concentrations (39% increase in AUC0-4 after intravenous infusion). In COPD patients with moderate to severe renal impairment (creatinine clearance of <50 mL/min), the intravenous administration of tiotropium resulted in doubling of the plasma concentrations (82% increase in AUC0-4), which was confirmed by plasma concentrations after dry powder inhalation. Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Spiriva HandiHaler should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6), and Use in Specific Populations (8.6)].
13 NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 0.059 mg/kg/day, in an 83-week inhalation study in female mice at doses up to 0.145 mg/kg/day, and in a 101-week inhalation study in male mice at doses up to 0.002 mg/kg/day. These doses correspond to approximately 25, 35, and 0.5 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
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 0.078 mg/kg/day or greater (approximately 35 times the RHDID on a mg/m2 basis). No such effects were observed at 0.009 mg/kg/day (approximately 4 times than the RHDID on a mg/m2 basis). The fertility index, however, was not affected at inhalation doses up to 1.689 mg/kg/day (approximately 760 times the RHDID on a mg/m2 basis). These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
Animal Toxicology and Pharmacology
Reproductive Toxicology Studies
No evidence of fetal structural alteration was observed in rats and rabbits at inhalation tiotropium doses of up to 1.471 and 0.007 mg/kg/day, respectively. These doses correspond to approximately 660 and 6 times the RHDID on a mg/m2 basis, respectively. However, in rats, 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 were observed at inhalation tiotropium doses of ≥0.078 mg/kg (approximately 35 times the RHDID on a mg/m2 basis). In rabbits, an increase in post-implantation loss was observed at an inhalation dose of 0.4 mg/kg/day (approximately 360 times the RHDID on a mg/m2 basis). Such effects were not observed at inhalation doses of 0.009 and up to 0.088 mg/kg/day in rats and rabbits, respectively. These doses correspond to approximately 4 and 80 times the RHDID on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
14 CLINICAL STUDIES
The Spiriva HandiHaler (tiotropium bromide inhalation powder) clinical development program consisted of six Phase 3 studies in 2663 patients with COPD (1308 receiving Spiriva HandiHaler): two 1-year, placebo‑controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These studies enrolled patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a forced expiratory volume in one second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less than or equal to 0.7.
Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5992 COPD patients. Long-term effects on lung function and other outcomes were also evaluated in the 4-year multicenter trial.
6-Month to 1-Year Effects on Lung Function
In the 1-year, placebo-controlled trials, the mean improvement in FEV1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1). Further improvements in FEV1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The mean peak improvement in FEV1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance.
In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial FEV1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV1) with Spiriva HandiHaler, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month treatment period.
*Means adjusted for center, treatment, and baseline effect. On Day 169, a total of 183 and 149 patients in the Spiriva HandiHaler and placebo groups, respectively, completed the trial. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward.
*Means adjusted for center, treatment, and baseline effect. On Day 92 (primary endpoint), a total of 151 and 69 patients in the Spiriva HandiHaler and ipratropium groups, respectively, completed through 3 months of observation. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward.
A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, regardless of whether Spiriva HandiHaler was administered in the morning or in the evening.
Throughout each week of the one-year treatment period in the two placebo-controlled trials, patients taking Spiriva HandiHaler had a reduced requirement for the use of rescue short-acting beta2-agonists. Reduction in the use of rescue short-acting beta2-agonists, as compared to placebo, was demonstrated in one of the two 6-month studies.
4-Year Effects on Lung Function
A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5992 COPD patients was conducted to evaluate the long-term effects of Spiriva HandiHaler on disease progression (rate of decline in FEV1). Patients were permitted to use all respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The patients were 40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV1 of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV1, as demonstrated by similar slopes of FEV1 decline over time (Figure 3).
Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV1 (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary function tests after Day 30 and non-missing baseline value were included in the analysis.
The effect of Spiriva HandiHaler on COPD exacerbations was evaluated in two clinical trials: a 4-year clinical trial described above and a 6-month clinical trial of 1829 COPD patients in a Veterans Affairs setting. In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization. The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 36% (range = 8% to 93%). Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. Spiriva HandiHaler significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo (27.9% vs 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99; p = 0.037). The proportion of patients with hospitalization due to COPD exacerbations in patients who used Spiriva HandiHaler compared to placebo was 7.0% vs 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056.
Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. Spiriva HandiHaler significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; p<0.002) compared to placebo. The median time to first exacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8) in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the Spiriva HandiHaler group.
16 HOW SUPPLIED/STORAGE AND HANDLING
Spiriva HandiHaler consists of Spiriva capsules and the HandiHaler device. Spiriva capsules contain 18 mcg of tiotropium and are light green, with the Boehringer Ingelheim company logo on the Spiriva capsule cap and TI 01 on the Spiriva capsule body, or vice versa.
The HandiHaler device is gray colored with a green piercing button. It is imprinted with Spiriva HandiHaler (tiotropium bromide inhalation powder), the Boehringer Ingelheim company logo. It is also imprinted to indicate that Spiriva capsules should not be stored in the HandiHaler device and that the HandiHaler device is only to be used with Spiriva capsules.
Spiriva capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. Spiriva capsules should always be stored in the blister and only removed immediately before use. The drug should be used immediately after the packaging over an individual Spiriva capsule is opened.
- carton containing 5 Spiriva capsules (1 unit-dose blister card) and 1 HandiHaler inhalation device (NDC 0597-0075-75) (institutional pack)
- carton containing 30 Spiriva capsules (3 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 0597-0075-41)
- carton containing 90 Spiriva capsules (9 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 0597-0075-47)
17 PATIENT COUNSELING INFORMATION
Instructions for Administering Spiriva HandiHaler
It is important for patients to understand how to correctly administer Spiriva capsules using the HandiHaler device [see Patient Counseling Information (17)]. Instruct patients that Spiriva capsules should only be administered via the HandiHaler device and the HandiHaler device should not be used for administering other medications. Remind patients that the contents of Spiriva capsules are for oral inhalation only and must not be swallowed.
Instruct patients always to store Spiriva capsules in sealed blisters and to remove only one Spiriva capsule immediately before use or its effectiveness may be reduced. Instruct patients to discard unused additional Spiriva capsules that are exposed to air (i.e., not intended for immediate use).
Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eye drops alone are not considered to be effective treatment.
|Do NOT swallow Spiriva capsules.|
Read the information that comes with your Spiriva HandiHaler before you start using it and each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.
- Spiriva HandiHaler is a prescription medicine used each day (a maintenance medicine) to control symptoms of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
- Spiriva HandiHaler helps make your lungs work better for 24 hours. Spiriva HandiHaler relaxes your airways and helps keep them open. You may start to feel like it is easier to breathe on the first day, but it may take longer for you to feel the full effects of the medicine. Spiriva HandiHaler works best and may help make it easier to breathe when you use it every day.
- Spiriva HandiHaler reduces the likelihood of flare-ups and worsening of COPD symptoms (COPD exacerbations). A COPD exacerbation is defined as an increase or new onset of more than one COPD symptom such as cough, mucus, shortness of breath, and wheezing that requires medicine beyond your rescue medicine.
- are allergic to tiotropium, ipratropium (Atrovent®), or any of the ingredients in Spiriva HandiHaler. See the end of this leaflet for a complete list of ingredients in Spiriva HandiHaler.
- raised red patches on your skin (hives)
- swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing
- have kidney problems.
- have glaucoma. Spiriva HandiHaler may make your glaucoma worse.
- have an enlarged prostate, problems passing urine, or a blockage in your bladder. Spiriva HandiHaler may make these problems worse.
- are pregnant or plan to become pregnant. It is not known if Spiriva HandiHaler could harm your unborn baby.
- are breast-feeding or plan to breast-feed. It is not known if Spiriva HandiHaler passes into breast milk. You and your doctor will decide if Spiriva HandiHaler is right for you while you breast-feed.
- have a severe allergy to milk proteins. Ask your doctor if you are not sure.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines and eye drops, vitamins, and herbal supplements. Some of your other medicines or supplements may affect the way Spiriva HandiHaler works. Spiriva HandiHaler is an anticholinergic medicine. You should not take other anticholinergic medicines while using Spiriva HandiHaler, including ipratropium. Ask your doctor or pharmacist if you are not sure if one of your medicines is an anticholinergic.
- Use Spiriva HandiHaler exactly as prescribed. Use Spiriva HandiHaler one time every day.
- Read the "Instructions for Use" at the end of this leaflet before you use Spiriva HandiHaler. Talk with your doctor if you do not understand the instructions.
- Do not swallow Spiriva capsules.
- Only use Spiriva capsules with the HandiHaler device.
- Do not use the HandiHaler device to take any other medicine.
- Spiriva HandiHaler comes as a powder in a Spiriva capsule that fits the HandiHaler device. Each Spiriva capsule, containing only a small amount of Spiriva powder, is one full dose of medicine.
- Separate one blister from the blister card. Then take out one of the Spiriva capsules from the blister package right before you use it.
- After the capsule is pierced, take a complete dose of Spiriva HandiHaler by breathing in the powder by mouth two times, using the HandiHaler device (take 2 inhalations from one Spiriva capsule). See the "Instructions for Use" at the end of this leaflet.
- Throw away any Spiriva capsule that is not used right away after it is taken out of the blister package. Do not leave the Spiriva capsules open to air; they may not work as well.
- If you miss a dose, take it as soon as you remember. Do not use Spiriva HandiHaler more than one time every 24 hours.
- If you use more than your prescribed dose of Spiriva HandiHaler, call your doctor or a poison control center.
- Do not let the powder from the Spiriva capsule get into your eyes. Your vision may get blurry and the pupil in your eye may get larger (dilate). If this happens, call your doctor.
- Spiriva HandiHaler can cause dizziness and blurred vision. Should you experience these symptoms you should use caution when engaging in activities such as driving a car or operating appliances or other machines.
- raised red patches on your skin (hives)
- swelling of the lips, tongue, or throat that may cause difficulty in breathing or swallowing
- Sudden narrowing and blockage of the airways into the lungs (bronchospasm). Your breathing suddenly gets worse.
- New or worsened increased pressure in the eyes (acute narrow-angle glaucoma). Symptoms of acute narrow-angle glaucoma may include:
- eye pain
- blurred vision
- seeing halos (visual halos) or colored images along with red eyes
- New or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include: difficulty passing urine, painful urination.
- upper respiratory tract infection
- dry mouth
- sinus infection
- sore throat
- non-specific chest pain
- urinary tract infection
- runny nose
- increased heart rate
- blurred vision
- Do not store Spiriva capsules in the HandiHaler device.
- Store Spiriva capsules in the sealed blister package at room temperature between 68°F to 77°F (20° to 25°C).
- Keep Spiriva capsules away from heat and cold (do not freeze).
- Store Spiriva capsules in a dry place. Throw away any unused Spiriva capsules that have been open to air.
General information about Spiriva HandiHaler
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Spiriva HandiHaler for a purpose for which it has not been prescribed. Do not give Spiriva HandiHaler to other people even if they have the same symptoms that you have. It may harm them.
For more information about Spiriva HandiHaler, go to www.Spiriva.com, or scan the code below, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.
COPD is a serious lung disease that includes chronic bronchitis, emphysema, or both. Most COPD is caused by smoking. When you have COPD, your airways become narrow. So, air moves out of your lungs more slowly. This makes it hard to breathe.
|Do not swallow Spiriva capsules.|
- Do not swallow Spiriva capsules.
- Spiriva capsules should only be used with the HandiHaler device and inhaled through your mouth (oral inhalation).
- Do not use your HandiHaler device to take any other medicine.
The parts of your HandiHaler device include:
(See Figure A)
Each Spiriva capsule is packaged in a blister. (See Figure B)
Taking your full daily dose of medicine requires 4 main steps.
Step 1. Opening your HandiHaler device:
After removing your HandiHaler device from the pouch:
Step 2. Inserting the Spiriva capsule into your HandiHaler device:
Each day, separate only 1 of the blisters from the blister card by tearing along the perforated line. (See Figure G)
Remove the Spiriva capsule from the blister:
Place the Spiriva capsule in the center chamber of your HandiHaler device. (See Figure I)
Close the mouthpiece firmly against the gray base until you hear a click. Leave the dust cap (lid) open. (See Figure J)
Step 3. Piercing the Spiriva capsule:
Step 4. Taking your full daily dose (2 inhalations from the same Spiriva capsule):
Breathe out completely in 1 breath, emptying your lungs of any air. (See Figure L)
Important: Do not breathe into your HandiHaler device.
With your next breath, take your medicine:
The rattle tells you that you breathed in correctly. If you do not hear or feel a rattle, see the section, “If you do not hear or feel the Spiriva capsule rattle as you breathe in your medicine."
To get your full daily dose, you must again, breathe out completely (See Figure N) and for a second time, breathe in (See Figure O) from the same Spiriva capsule.
Important: Do not press the green piercing button again.
Remember: To get your full medicine dose each day, you must breathe in 2 times from the same Spiriva capsule. Make sure you breathe out completely each time before you breathe in from your HandiHaler device.
Caring for and storing your Spiriva HandiHaler:
If you do not hear or feel the Spiriva capsule rattle as you breathe in your medicine:
Do not press the green piercing button again.
Hold your HandiHaler device with the mouthpiece pointed up and tap your HandiHaler device gently on a table. (See Figure Q)
Check to see that the mouthpiece is completely closed. Breathe out completely before deeply breathing in again with the mouthpiece in your mouth. (See Figure O)
If you still do not hear or feel the Spiriva capsule rattle after repeating the above steps:
Cleaning your HandiHaler device:
Clean your HandiHaler device as needed. (See Figure R)
|Helpful Hints to help ensure that you are properly taking your full daily dose of Spiriva HandiHaler:
For more information, ask your doctor or pharmacist, or go to www.Spiriva.com, or scan the code below, or call 1-800-542-6257.
tiotropium bromide capsule
|Labeler - Boehringer Ingelheim Pharmaceuticals Inc. (603175944)|
|Registrant - Boehringer Ingelheim Pharmaceuticals Inc. (603175944)|
|Boehringer Ingelheim Roxane Inc.||058839929||PACK(0597-0075), LABEL(0597-0075)|
|Boehringer Ingelheim Pharma GmbH and Co. KG||551147440||API MANUFACTURE(0597-0075), MANUFACTURE(0597-0075), ANALYSIS(0597-0075)|