Spiriva 18 mcg

Interactions with drugs administered concomitantly with tiotropium are not expected due to the low dose and low steady state plasma concentration of tiotropium (18 μg, C_ss 2-20 pg/mL) and the lack of cytochrome P450 inhibition by tiotropium. Similarly, effects of concomitantly administered drugs on tiotropium metabolism are not expected due to the minor contribution of enzymatic metabolism of tiotropium.

Although no formal drug interaction studies have been performed, SPIRIVA has been used concomitantly with other drugs without additional adverse drug reactions. These include sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids commonly used in the treatment of COPD.

The co-administration of SPIRIVA with other anticholinergic containing drugs has not been studied and is, therefore, not recommended.

Tiotropium does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 even in supratherapeutic concentrations of 1 μMol/L (=0.4 μg/mL), which makes clinically relevant metabolic interactions by tiotropium extremely unlikely.

Counselling by doctors on smoking cessation should be the first step in treating patients with COPD, who smoke, independent of the clinical presentation i.e. chronic bronchitis (with or without airflow limitation) or emphysema. Cessation of smoking produces dramatic symptomatic benefits and has been shown to confer a survival advantage.

The recommended dosage of SPIRIVA (tiotropium bromide monohydrate) is inhalation of the contents of one capsule (18 μg) once daily. The capsule must not be swallowed.

SPIRIVA should be administered once daily, at the same time of day, by inhalation only through the HandiHaler inhalation device. To ensure proper administration of SPIRIVA, the doctor or other qualified health care professional should teach the patient how to operate the HandiHaler inhalation device (see Information for the Patient).

Patients should be advised that if they forget to take a dose, they should take one as soon as they remember but do not take two doses at the same time or on the same day. Then take the next dose as usual.

Patients should be advised that if they take more SPIRIVA 18 microgram than they should—talk to their doctor immediately.

The following undesirable effects have been identified primarily by reporting in the worldwide post-marketing experience: dysphonia, epistaxis, palpitations, dizziness, rash, urticaria, pruritus.

Post-marketing adverse experiences also include rare reports of syncope/loss of consciousness, chest pain, atrial fibrillation, myocardial infarction, anginal pectoris, tachycardia, arrhythmia, and cardiac failure. 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

cataract.

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

dysphonia, paraesthesia.

hypercholesterolemia, hyperglycemia.

herpes zoster.

allergic reaction, leg pain.

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.

tachycardia.

depression.

laryngitis.

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

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:

skeletal pain.

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.

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.

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

angina pectoris (including aggravated angina pectoris).

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.

The HandiHaler inhalation device is a reusable plastic device used for the administration of SPIRIVA capsules. It is gray coloured with “HandiHaler”, “Boehringer Ingelheim”, and the Boehringer Ingelheim company logo, printed on the front face.

The HandiHaler operates with flow rates as low as 20 L/min. All patients, regardless of their disease severity, achieved sufficient flows through the HandiHaler. To use the delivery system, a SPIRIVA capsule is placed in the center chamber of the HandiHaler inhalation device and the capsule is pierced by pressing and releasing the green piercing button on the side of the device. The tiotropium formulation is dispersed into the air stream when the patient inhales slowly and deeply through the mouthpiece. The HandiHaler inhalation devices are available individually.

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).

Animal data only.

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.

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

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.

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 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.

Impaired liver function is not expected to have any clinically 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.

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.

The high renal clearance of tiotropium suggests the possibility of a decreased renal elimination in the elderly (≥69 years) as a result of decreased renal function with age. To investigate this, pharmacokinetic parameters were determined for different age groups.

Although highly variable, the results suggested that tiotropium plasma concentrations were moderately increased in the elderly COPD patients for both C_5min and C_2hr. There is an age dependent decrease in the fraction of tiotropium excreted in the urine. Total urinary excretion decreases from about 14% in young healthy volunteers to about 7% in the older COPD patients, corresponding to decreased renal clearance with age from 326 mL/min to 163 mL/min, respectively. This decrease in tiotropium renal clearance with advanced age exceeded the change in creatinine clearance; creatinine clearance was approximately 113 mL/min in young healthy volunteers and 61 mL/min in elderly COPD patients. This suggested that the renal secretion of tiotropium was more sensitive to age than glomerular filtration.

The absolute bioavailability of SPIRIVA after dry powder inhalation is 19.5% and is negligible after oral administration (2-3%). The apparent volume of distribution is 32 L/kg suggesting extensive tissue binding.

Tiotropium is moderately bound to human plasma proteins (72%). This binding is not of the restrictive type considering the high renal clearance of 669 mL/min.

The pharmacokinetic profile of SPIRIVA (tiotropium bromide monohydrate) supports that plasma concentrations are very low following inhalation of an 18 μg dose; although the terminal elimination half life is between 5-7 days, there is only moderate accumulation upon repeated once daily dosing.

SPIRIVA (tiotropium bromide monohydrate) is a long acting, muscarinic receptor antagonist that is used as a once-daily inhaled bronchodilator for the treatment of bronchospasm associated with Chronic Obstructive Pulmonary Disease (COPD). SPIRIVA is a quaternary ammonium molecule with a duration of action sufficient to provide 24 hours of bronchoprotection with once-a-day inhalational administration. In vitro studies using recombinant human receptors as well as animal and human tissue preparations, showed that tiotropium is a potent, reversible, M₃-selective muscarinic receptor antagonist, with no other receptor interactions detected at clinically relevant concentrations.

Muscarinic acetylcholine receptors are widely distributed throughout the body and serve a variety of important functions. Stimulation of muscarinic receptors in response to the activation of the parasympathetic nervous system is the dominant neural bronchoconstrictor pathway in all mammals, including humans. In fact, the reversal of chronic obstructive disease with antimuscarinic agents is a well established therapeutic approach.

There are five subtypes (M₁–M₅) of muscarinic receptors which exhibit distinct pharmacology and tissue distribution. M₃ receptors predominate in visceral smooth muscles and typically mediate the direct contractile effects of acetylcholine. In addition, M₃, as well as M₁ receptors, are also found in the central nervous system and autonomic ganglia. M₂ receptors predominate in the heart and mediate the bradycardic effects of acetylcholine. They are also found on parasympathetic nerve terminals where their activation inhibits the release of acetylcholine. The physiological roles of M₄ and M₅ receptors are still uncertain.

The long duration of action of tiotropium is thought to be due to its high affinity to, and slow dissociation kinetics from, the muscarinic M₃-receptor subtype. Tiotropium has a higher affinity for human muscarinic 3 (hM₃)-receptors (KD value:8.89 pmol/L) than for hM₂-receptors (KD value:31.96 pmol/L). In addition, and most importantly, tiotropium dissociates very slowly from hM₃-receptors. Dissociation half-lives of the receptor-ligand complex are 27.1 hours for hM₃-receptors and 3.6 hours for hM₂-receptors. For comparison, dissociation half-lives of ipratropium are 0.22 and 0.04 hours for hM₃- and hM₂-receptors, respectively. As an N-quaternary anticholinergic, tiotropium is broncho-selective when administered by inhalation, demonstrating an acceptable therapeutic range before giving rise to systemic anticholinergic effects.

Urinary data in healthy subjects demonstrate that tiotropium was excreted with a geometric mean elimination half-life of 5.7 days (3.2-7.3 days) after intravenous, and 4.8 days (3.6-6.2 days) after inhalation. The long elimination half-life indicates a slow redistribution process, and it is likely that the slow dissociation from muscarinic receptors contributes to the slow redistribution. Indication of active renal secretion is based on a renal clearance of 669 mL/min after intravenous infusion and 486 mL/min after inhalation, while calculated creatinine clearance was 118 mL/min and 113 mL/min, respectively. Urinary recovery was approximately 74% as unchanged substance. Total clearance was 880 mL/min.

In common with all other drugs that undergo predominantly renal excretion, renal impairment was associated with reduced renal drug clearance and increased plasma drug concentrations. Mild renal impairment (CL_CR 50-80 mL/min) which is often seen in elderly patients did not lead to a clinically significant change in tiotropium pharmacokinetics. However, in COPD patients with moderate to severe renal impairment (CL_CR <50 mL/min), the intravenous administration of tiotropium resulted in doubling of the plasma concentrations seen in patients with normal renal function (82% increase in AUC_0-4h), which was confirmed by plasma concentrations after dry powder inhalation.

In a study conducted to investigate the pharmacokinetics of tiotropium in patients with varying degrees of renal impairment in comparison to healthy volunteers, a single dose of tiotropium (4.8 μg) was administered as an intravenous infusion over 15 minutes. The results indicate that renal tiotropium clearance decreased with creatinine clearance. Tiotropium plasma concentrations (AUC_0-4h) were 39, 81 and 94% higher in mild, moderate and severe renal impairment when compared to control subjects. SPIRIVA should be used in patients with moderate to severe renal impairment only if the expected benefit outweighs the potential risk.

To assess potential sex-related effects on tiotropium pharmacokinetics, plasma and urine samples were collected from a subset of COPD patients at selected centres for assessment of tiotropium concentrations. Although there was a slight trend to higher plasma concentrations in females, it is considered that male and female COPD patients showed no significant differences in drug plasma concentrations or urinary excretion of tiotropium.

The drug is not metabolized to a great extent; the majority of the drug is excreted as the parent compound.

Tiotropium is predominantly eliminated via renal secretion of unchanged drug. Seventy-four percent of an intravenous dose was recovered in urine (Ae_0-∞) after intravenous infusion in healthy young male subjects. The indication of active renal secretion is based on a renal clearance of 669 mL/min after intravenous infusion and 486 mL/min after inhalation, while calculated creatinine clearance was 118 mL/min and 113 mL/min, respectively.

The tiotropium ester was shown to be non-enzymatically cleaved and enzymatically metabolized in animals. In humans, a small part (up to 20%) might also be metabolized in the liver. Tiotropium does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 even in supratherapeutic concentrations of 1 μMol/L (=0.4 μg/mL), which makes clinically relevant metabolic interactions by tiotropium extremely unlikely.

For tiotropium, absolute bioavailability was most reliably estimated from the total urinary excretion values in healthy volunteers rather than plasma concentrations. The absolute oral bioavailability of tiotropium is 2-3% for a 64 μg dose. The low extent of absorption and low oral bioavailability is expected based on animal experiments with radiolabeled drug. The absolute bioavailability of tiotropium after an inhaled dose of 108 μg (three 36 μg inhalation capsules) is 19.5%. Low oral bioavailability is a definite advantage in limiting systemic absorption following obligate ingestion of a portion of an orally-inhaled drug.

Study results supported that pharmacodynamic steady state was attained within the first week of dosing; additionally, the multiple dose studies supported the once daily dosing regimen for tiotropium administered by inhalation of a dry powder formulation.

The clinical pharmacology studies confirmed the intended pharmacodynamic effect of bronchodilation in subjects with COPD. The bronchodilation following inhalation of tiotropium is primarily a site-specific effect, rather than a systemic effect. Trough forced expiratory volume in one second (FEV₁), 24 hours after a previous dose, (i.e. prior to subsequent dosing) remained significantly increased over baseline relative to placebo; the majority of the maintenance bronchodilation was achieved within a few days of treatment. Pharmacodynamic steady state was attained within the first week of once-daily dosing. Repeated inhalation of SPIRIVA has not been linked with tolerance towards bronchodilatory effects of the drug. Bronchodilatory effects gradually returned to baseline levels upon cessation of treatment with no evidence of rebound. Multiple dose studies supported the once daily dosing regimen for tiotropium administered by inhalation of a dry powder formulation. Studies with supratherapeutic doses have confirmed that reduced salivation is among the most sensitive effects. This clinical physiologic effect is mirrored by reports of dry mouth.

The clinical development program included four one-year and two six-month randomized, double-blind studies in 2663 patients, 1308 receiving SPIRIVA. The one-year program consisted of two placebo-controlled and two ipratropium-controlled trials. The six-month trials were salmeterol and placebo-controlled. All studies included measurements of lung function as well as health outcome measures of dyspnea, exacerbations and health-related quality of life.

SPIRIVA administered once daily provided significant improvement in lung function (forced expiratory volume in one second, FEV₁; and forced vital capacity, FVC) within 30 minutes following the first dose and was maintained for 24 hours whether SPIRIVA was administered in the morning or in the evening. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. The bronchodilator effects of SPIRIVA were maintained throughout the one-year period of administration with no evidence of tolerance.

Pharmacokinetics in children were not investigated as tiotropium development is currently restricted to therapy for COPD in adults.

After chronic, once-daily inhalation of tiotropium (18 μg) by COPD patients, pharmacokinetic steady state was reached after 2-3 weeks with no accumulation thereafter. Maximum steady state tiotropium plasma concentrations (17-19 pg/mL) were observed 5 minutes after inhalation and decreased to approximately 3-4 pg/mL at trough. At steady state, urinary excretion of unchanged tiotropium during the first 4 hours following administration accounted for 1.42% (88.7% gCV) and 1.97% (74.4% gCV) in older and younger patients, respectively.