SPIRIVA (tiotropium bromide monohydrate) is indicated for:

• long term, once daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

  
  

Relief of dyspnea was evaluated using the Transition Dyspnea Index (TDI). A TDI score of ≥1 unit was considered clinically significant, and patients with this score were considered responders. In the one-year and six-month trials, there was a statistically significant higher percentage of responders treated with SPIRIVA than placebo.

 

As expected for all predominantly renally excreted drugs, advanced age (≥65 years) was associated with a decrease of tiotropium renal clearance which may be explained by decreased renal function. Tiotropium excretion in urine after inhalation decreased from 14% in young healthy volunteers to about 7% in the older COPD patients. However, plasma concentrations did not change significantly with advancing age within COPD patients (≥69 years vs ≤58 years) if compared to inter- and intra-individual variability (43% increase in AUC_0-4 after dry powder inhalation). Consequently, geriatric patients can use tiotropium at the recommended dose.

Safety and effectiveness of SPIRIVA in patients less than 18 years of age were not studied.

SPIRIVA (tiotropium bromide monohydrate) is contraindicated in:

• patients with a history of hypersensitivity to atropine or its derivatives (e.g. ipratropium or oxitropium), or to the excipient lactose monohydrate (see Dosage Forms, Composition and Packaging).

  
  

 

SPIRIVA (tiotropium bromide monohydrate) should not be used more frequently than once daily.

SPIRIVA, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy.

Immediate hypersensitivity reactions such as skin rash, urticaria, angioedema of the lip, tongue and face, bronchospasm, and oropharyngeal edema may occur after administration of SPIRIVA.

As with other anticholinergic drugs, SPIRIVA should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.

No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness or blurred vision may influence the ability to drive and use machinery.

This product contains 5.5 mg of lactose monohydrate per capsule.

Animal data only.

Patients should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these symptoms develop, they should consult a doctor immediately. Miotic drops alone are not considered to be effective treatment.

As plasma concentration increases with decreased renal function in patients with moderately to severe renal impairment (creatinine clearance ≤50 mL/min), SPIRIVA should be used only if the expected benefit outweighs the potential risk. There is no long term experience in patients with severe renal impairment (see Pharmacokinetics).

Inhaled medicines may cause inhalation-induced bronchospasm. If this occurs, treatment with SPIRIVA should be discontinued immediately.

There are no studies of SPIRIVA in pregnant women. Because animal reproduction studies are not always predictive of human response, SPIRIVA should be used during pregnancy only if the benefits outweigh any possible risk to the unborn child.

Oral reproduction studies with tiotropium were performed at doses up to 500 mg/kg in rats and 100 mg/kg in rabbits. These doses correspond, in each species, to about 215 000 and 86 000 times the Maximum Recommended Human Dose (MRHD) respectively, on a mg/m² basis. Inhalation reproduction studies with tiotropium were conducted in rats and rabbits at doses of 2.0 and 0.5 mg/kg/day (about 860 and 430 times the MRHD on a mg/m² basis). These studies demonstrated no evidence of teratogenic effects as a result of tiotropium administration.

The safety and effectiveness of SPIRIVA have not been studied during labor and delivery.

Based on lactating rodent studies, a small amount of tiotropium (1.9%) is excreted in milk over two days. Clinical data from nursing women exposed to SPIRIVA are not available. SPIRIVA should not be used in nursing women unless the expected benefit outweighs any possible risk to the infant.

Safety and effectiveness of SPIRIVA in patients less than 18 years of age were not studied.

Adverse reactions to SPIRIVA are similar in nature to reactions to other anticholinergic bronchodilators. Many of the listed undesirable effects can be assigned to the anticholinergic properties of SPIRIVA. The most commonly reported adverse drug reaction was dry mouth. In the one-year and six-month studies, the discontinuation rate due to dry mouth was 0.3%. Other adverse reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, increased heart rate, supraventricular tachycardia, atrial fibrillation, blurred vision, acute glaucoma, urinary difficulty and urinary retention.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Of the 1456 patients in the four one-year controlled clinical trials and the 1207 patients in the two six-month controlled clinical trials, 906 and 402 patients, respectively, were treated with SPIRIVA at the recommended dose of 18 μg once a day.

Four multi-center, one-year, controlled studies have evaluated once daily doses of SPIRIVA in patients with COPD. The following table shows adverse events that occurred with a frequency of ≥3% in the SPIRIVA group in the placebo-controlled trials, and where the rates in the SPIRIVA group exceeded placebo by ≥1%. The frequency of corresponding events in the ipratropium-controlled trials are included for comparison.

Table 1: SPIRIVA

Adverse Event Incidence (% Patients) In One-Year COPD Clinical Trials

^a. Dry mouth was usually mild and led to discontinuation of therapy in 0.3% of SPIRIVA treated patients.

Arthritis, coughing and influenza-like symptoms occurred at a rate of ≥3% in the SPIRIVA treatment group, but were <1% in excess of the placebo groups.

Other events that occurred in the SPIRIVA group at a frequency of 1-3% in the placebo-controlled trials and where the rates exceeded that in the placebo group include:

allergic reaction, leg pain.

dysphonia, paraesthesia.

gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis).

hypercholesterolemia, hyperglycemia.

skeletal pain.

angina pectoris (including aggravated angina pectoris).

depression.

herpes zoster.

laryngitis.

cataract.

Adverse reactions with incidences >0.1% and <1% in excess of placebo include:

tachycardia.

difficulty urinating and urinary retention (in men with predisposing factors).

angio-oedema (1 of 906 patients in the four one-year trials).

As with other orally inhaled drugs, pharyngo-oral irritation and paradoxical bronchospasm were observed.

Two multi-center, six-month, salmeterol and placebo-controlled studies have evaluated once daily doses of SPIRIVA in patients with COPD. The following table shows adverse events where the frequency was ≥3% in the SPIRIVA 18 µg once daily group and where the rates in the SPIRIVA group exceeded placebo by at least 1%.

Table 2: SPIRIVA

Adverse Event Incidence (% Patients^a) in Six-Month COPD Clinical Trials

Body System Event	Combined Data (Trials 205.130 & 205.137)
	SPIRIVA [n=402]	Salmeterol [n=405]	Placebo [n=400]
Body as a Whole
Accidents	4.2	5.2	2.5
Back Pain	4.0	4.0	3.0
Headache	6.5	6.9	4.5
Influenza Like Symptoms	6.7	5.2	4.0
Gastrointestinal System Disorders
Dry Mouth	8.2	1.7	2.3
Respiratory System (upper)
Pharyngitis	4.5	3.5	3.0
Upper Respiratory Tract Infection	19.4	17.0	16.0
Respiratory System (lower)
Coughing	5.2	5.9	3.5

^a. Percentages are calculated using total number of patients treated as the denominator.

Table 3 and Table 4 included in this section are based on pooled data from all 19 randomized placebo-controlled clinical trials in phase III and IV with treatment periods ranging between four weeks and one year. The cutoff date for these analyses was April 2005. Under each treatment, 'N with event' is the number of patients with the selected adverse drug reaction or adverse event. 'Exposure' is defined as cumulative time of patients on treatment, i.e. all days from the start of treatment until the day of the last inhalation of study treatment. The 'rate' presented is the rate of (first) events per 100 patient-years. Estimates and confidence intervals for the calculation of 'rate ratios' are based on stratification by study. The values presented are the Mantel-Haenszel values.

The adverse reactions included in Table 3 were attributed to the administration of SPIRIVA based on reasonable grounds to suggest a causal relationship, including evidence from post marketing experience. Table 3 additionally provides incidence rates and rate ratios for these terms as calculated in the dataset of pooled placebo-controlled clinical trials, regardless of the assessment of causality in any individual case.

Table 3: SPIRIVA

Exposure-Adjusted-Incidence and Rate Ratio (Overall study population; adverse reactions)

^a. Usually mild, which often resolved with continued treatment.
^b. As with other inhaled treatment.
^c. Usually in men with predisposing factors.
^d. Collapsed terms consist of various relevant preferred terms (MedDRA).
^e. Mantel Haenszel rate ratio estimator.

Table 4 shows reported adverse events from clinical trials for which causality has not been established. They have been selected on the basis of their potential relevance as important health outcomes or their incidence relative to placebo.

Table 4: SPIRIVA

Exposure-Adjusted-Incidence and Rate Ratio (Overall Study Population; Unlisted Adverse Events of Interest)

^a. Collapsed terms consist of various relevant preferred terms (MedDRA).
^b. Mantel Haenszel rate ratio estimator.

Table 5 and Table 6 included in this section are based on pooled data from all 19 randomized placebo-controlled clinical trials in phase III and IV with treatment periods ranging between four weeks and one year. The cutoff date for these analyses was April 2005. Only patients with a reported history of cardiac disease (excluding sole diagnosis of hypertension or other vascular disorders) prior to recruitment to a SPIRIVA study are included. 47% of patients included in this subgroup analysis had a history of myocardial ischemia excluding myocardial infarction, 18% had a history of myocardial infarction. Additionally, 19% of patients in this subgroup analysis had a reported history of cardiac failure, and 12% of patients reported a history of atrial fibrillation.

The adverse reactions included in Table 5 were attributed to the administration of SPIRIVA based on reasonable grounds to suggest a causal relationship, including evidence from post marketing experience. Table 3 additionally provides incidence rates and rate ratios for these terms as calculated in the dataset of pooled placebo-controlled clinical trials, regardless of the assessment of causality in any individual case.

Table 5: SPIRIVA

Exposure-Adjusted-Incidence and Rate Ratio (Subgroup with cardiac disease; adverse reactions)