Spiriva (Tiotropium Bromide Monohydrate Inhalation) - Description and Clinical Pharmacology

Do Not Swallow Spiriva Capsules
For Use With HandiHaler Device Only

FOR ORAL INHALATION ONLY

Prescribing Information

DESCRIPTION

SPIRIVA® HandiHaler® (tiotropium bromide inhalation powder) consists of a capsule dosage form containing a dry powder formulation of tiotropium intended for oral inhalation only with the HandiHaler device.

Each light green, hard gelatin SPIRIVA capsule contains 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate as the carrier.

The dry powder formulation within the SPIRIVA capsule is intended for oral inhalation only.

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[3.3.1.0^2,4]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 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 (2L total). In a study of 26 adult patients with chronic obstructive pulmonary disease (COPD) and severely compromised lung function [mean FEV₁ 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16%–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.

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’s Instructions for Use).

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 were dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.

Pharmacokinetics

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.

Absorption

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. Food is not expected to influence the absorption of tiotropium for the same reason. Oral solutions of tiotropium have an absolute bioavailability of 2–3%. Maximum tiotropium plasma concentrations were observed five minutes after inhalation.

Distribution

Tiotropium shows a volume of distribution of 32 L/kg, indicating that the drug binds extensively to tissues. The drug is bound by 72% to plasma proteins. At steady state, peak tiotropium plasma levels in COPD patients were 17-19 pg/mL when measured 5 minutes after dry powder inhalation of an 18 mcg dose and decreased rapidly in a multi-compartmental manner. Steady-state trough plasma concentrations were 3–4 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.

Biotransformation

The extent of biotransformation 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 bind 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.

Elimination

The terminal elimination half-life of tiotropium is 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 is mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion is 14% of the dose, the remainder being mainly non-absorbed drug in the gut which is 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 2–3 weeks with no accumulation thereafter.

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 AUC_0–4h, a 28% decrease in the renal clearance of tiotropium and no significant change in the C_max and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium. Therefore, no clinically significant interaction occurred between tiotropium and cimetidine or ranitidine.

Electrophysiology

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 30–60 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.

Special Populations

Elderly Patients

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 AUC_0–4 after dry powder inhalation), which was not significant when considered in relation to inter- and intra-individual variability (see DOSAGE AND ADMINISTRATION).

Hepatically-impaired Patients

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied. However, hepatic insufficiency is not expected to have relevant influence on tiotropium pharmacokinetics. Tiotropium is predominantly cleared by renal elimination (74% in young healthy volunteers) and by simple non-enzymatic ester cleavage to products that do not bind to muscarinic receptors (see DOSAGE AND ADMINISTRATION).

Renally-impaired Patients

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 (CrCl 50–80 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 (CrCl <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 (see DOSAGE AND ADMINISTRATION and PRECAUTIONS).

CLINICAL STUDIES

The SPIRIVA HandiHaler (tiotropium bromide inhalation powder) clinical development program consisted of six Phase 3 studies in 2,663 patients with COPD (1,308 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 an 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.

In these studies, SPIRIVA HandiHaler, administered once-daily in the morning, provided improvement in lung function (forced expiratory volume in one second, FEV₁), with peak effect occurring within 3 hours following the first dose.

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 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.

Results of each of the one-year ipratropium-controlled trials were similar to the results of the one-year placebo-controlled trials. The results of one of these trials are shown in Figure 2.

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.