Spiriva

Spiriva®

Tiotropium 18 mcg

Presentation

Inhalation powder, hard capsules. Light green hard capsules, containing a white or yellowish white powder, with product code (TI 01) and company logo printed on the capsule. Each capsule contains 22.5 mcg of tiotropium bromide monohydrate equivalent to 18 mcg of tiotropium.

Uses

Actions

Pharmacotherapeutic group: Anticholinergic
ATC code: R03B B

Tiotropium is a long-acting, specific antimuscarinic agent, in clinical medicine often called an anticholinergic. It has a similar affinity to the subtypes of muscarinic receptors M₁ to M₅. In the airways, inhibition of M₃-receptors at the smooth muscle results in relaxation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In pre-clinical in vitro as well as in vivo studies bronchoprotective effects were dose-dependent and lasted longer than 24 hours. The long duration of effect is likely to be due to its very slow dissociation from M₃-receptors, exhibiting a significantly longer dissociation half-life than that seen with ipratropium. As an N-quaternary anticholinergic tiotropium is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before giving rise to systemic anticholinergic effects. Dissociation from M₂-receptors is faster than from M₃, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M₃ over M₂. The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.

The bronchodilation following inhalation of tiotropium is primarily a local effect (on the airways), not a systemic one.

The clinical development program included four one-year and two six-month randomised, double-blind studies in 2663 patients (1308 receiving SPIRIVA). The one-year program consisted of two placebo-controlled (fig 1) and two ipratropium controlled trials (fig 2). The two six-month trials each were both, salmeterol and placebo controlled (fig 3). These studies included evaluation of lung function and health outcome measures of dyspnoea, exacerbations of COPD and patient's assessment of their health-related quality of life.

In the aforementioned studies, 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. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. SPIRIVA significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings.

The improvement in lung function with SPIRIVA was demonstrated throughout the period of administration in the six long-term trials (Figures 1-3). [44] These improvements were maintained with no evidence of tolerance.

Figure 1: Mean FEV₁ Over Time (prior to and after administration of study drug) on Days 1 and 344
in Two 1-Year Placebo-Controlled Trials*

Study A [1]

 *Means are adjusted for centre and baseline effects.

Study B [2]

*Means are adjusted for centre and baseline effects.

Figure 2: Mean FEV₁ Over Time (prior to and after administration of study drug) on Days 1 and 364 in
Two 1-Year Ipratropium-Controlled Trials*

Study A [3]

*Means are adjusted for centre and baseline effects.

Study B [4]

*Means are adjusted for centre and baseline effects.

Figure 3: Mean FEV₁ Over Time (prior to and after administration of study drug) on Days 1 and 169 in
Two 6-Month Salmeterol- and Placebo-Controlled Trials*

Study A [24]

*Means are adjusted for centre and baseline effects.

Study B [8]

*Means are adjusted for centre and baseline effects.

A randomised, placebo-controlled clinical study in 105 COPD patients demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether SPIRIVA was administered in the morning or in the evening.

The following health outcome effects were demonstrated in the long-term (6 month and 1 year) trials:

SPIRIVA significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index). This improvement was maintained throughout the treatment period.

SPIRIVA significantly reduced the number of COPD exacerbations and delayed the time to first exacerbation in comparison to placebo.

SPIRIVA significantly improved health-related quality of life as demonstrated by the disease-specific St. George's Respiratory Questionnaire. This improvement was maintained throughout the treatment period.

Additionally, in the one-year placebo controlled trials SPIRIVA significantly reduced the number of hospitalisations associated with COPD exacerbations and delayed the time to first hospitalisation.

Pharmacokinetics

Tiotropium is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium is administered by dry powder inhalation. Generally with the inhaled route of administration, the majority of the delivered dose is deposited in the gastro-intestinal tract, and to a lesser extent in the intended organ of the lung. Many of the pharmacokinetic data described below were obtained with higher doses as 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 gastro-intestinal 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: The drug is bound by 72 % to plasma proteins and shows a volume of distribution of 32 L/kg. At steady state, tiotropium plasma levels in COPD patients at peak were 17 - 19 pg/ml when measured 5 minutes after dry powder inhalation of a 18 microgram 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 penetrate the blood-brain barrier to any relevant extent.

Biotransformation: The extent of biotransformation is small. This is evident from a urinary excretion of 74 % of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, both not binding to muscarinic receptors.

In-vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (<20 % of dose after intravenous administration) is metabolised by cytochrome P450 dependent oxidation and subsequent glutathione conjugation to a variety of Phase II-metabolites. This enzymatic pathway can be inhibited by the CYP450 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium even in supra-therapeutic concentrations does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.

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 interindividual 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 gut that is eliminated via the faeces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating 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.

Linearity/nonlinearity: Tiotropium demonstrates linear pharmacokinetics in the therapeutic range after both intravenous administration and dry powder inhalation.

Elderly Patients: As expected for all predominantly renally excreted drugs, 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), however plasma concentrations did not change significantly with advancing age within COPD patients if compared to inter- and intra-individual variability (43 % increase in AUC_0-4h after dry powder inhalation).

Renally Impaired Patients: In common with all other drugs that undergo predominantly renal excretion, renal impairment was associated with increased plasma drug concentrations and reduced renal drug clearance after both intravenous infusion and dry powder inhalations. Mild renal impairment (CL_CR 50-80 ml/min) which is often seen in elderly patients increased tiotropium plasma concentrations slightly (39 % increase in AUC_0-4h after intravenous infusion). 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 (82 % increase in AUC_0-4h ), which was confirmed by plasma concentrations after dry powder inhalation.

Hepatically Impaired Patients: Liver insufficiency is not expected to have any relevant influence on tiotropium pharmacokinetics. Tiotropium is predominantly cleared by renal elimination (74% in young healthy volunteers) and simple non-enzymatic ester cleavage to pharmacologically inactive products.

Indications

Spiriva is indicated for the long term once daily maintenance treatment of bronchospasm and dyspnoea associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Spiriva reduces the frequency of exacerbations and improves health-related quality of life.

Dosage and Administration

The recommended dosage of Spiriva is inhalation of the contents of one capsule once daily with the HandiHaler device at the same time of day (see instructions for use).

Spiriva capsules must not be swallowed.

Special Populations:

Elderly patients can use Spiriva at the recommended dose.

Renally impaired patients can use Spiriva at the recommended dose. However, as with all predominantly renally excreted drugs, Spiriva use should be monitored closely in patients with moderate to severe renal impairment.

Hepatically impaired patients can use Spiriva at the recommended dose.

Paediatric patients: There is no experience with Spiriva in infants and children and therefore should not be used in this age group.

Contraindications

Spiriva inhalation powder is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium or to any component of this product.

Warnings and Precautions

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 may occur after administration of Spiriva inhalation powder.

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

Inhaled medicines may cause inhalation-induced bronchospasm.

As with all predominantly renally excreted drugs, Spiriva use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of ≤ 50 ml/min).

Patients must be instructed in the correct administration of SPIRIVA® capsules. Care must be taken not to allow the powder to enter into the eyes. Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop specialist advice should be sought immediately. Miotic eye drops are not considered to be effective treatment.

Spiriva should not be used more frequently than once daily.

Spiriva capsules are to be used only with the HandiHaler device.

Pregnancy and lactation

For Spiriva, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / foetal development, parturition or postnatal development.

Clinical data from nursing women exposed to Spiriva are not available. Based on lactating rodent studies, a small amount of Spiriva is excreted in milk.

Therefore, Spiriva should not be used in pregnant or nursing women unless the expected benefit outweighs any possible risk to the unborn child or the infant.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, on the basis of the pharmacodynamic and reported undesirable effects profiles at the recommended dose, there is no evidence for a potential influence on the ability to drive and use machines.

Adverse Effects

The undesirable effects listed below were attributed to the administration of SPIRIVA based on reasonable grounds to suggest a causal relationship. The frequencies given below are reporting incidences regardless of the assessment of causality in any individual case. The information is based on pooled data from controlled clinical trials with treatment periods ranging between four weeks and one year . These studies involved 2,706 patients in placebo-controlled trials and 3,696 patients in placebo-controlled plus active-controlled trials who have been treated with SPIRIVA (see Appendix 1, Table 1).

Table 1: Number (%) of Patients with Adverse Reactions¹ by Treatment at Onset, MedDra System Organ Class and Preferred Term for COPD in Phase III One-Year Trials

¹ reported incidences of all listed adverse events i.e. events in which there are reasonable medical grounds to suggest a causal relationship with tiotropium, are shown, regardless of the assessment of causality for any individual case.

Gastro-intestinal disorders:
≥ 1% and < 10%: dry mouth, usually mild, which often resolved with continued treatment.
≥ 0.1% and < 1%: constipation.

Respiratory, thoracic and mediastinal disorders:
>1% and < 10%: cough, throat irritation and other local irritation (as with other inhaled treatment)
≥ 0.1% and < 1%: hoarseness, epistaxis

Cardiac disorders
>0.1% and < 1%: tachycardia
≥ 0.01% and < 0.1%: supraventricular tachycardia, atrial fibrillation*, palpitations

Renal and urinary disorders:
>0.1% and < 1%: difficulty urinating and urinary retention (usually in men with predisposing factors)

Nervous systems disorders:
dizziness

Skin and subcutaneous tissue disorders, Immune system disorders:
≥ 0.01% and < 0.1%: rash*, urticaria, pruritus, angio-oedema, and other hypersensitivity reactions

Most of the above mentioned adverse reactions can be attributed to the anticholinergic properties of SPIRIVA. Other anticholinergic effects such as blurred vision and acute glaucoma may occur.

As with other inhaled therapy, inhalation-induced bronchospasm may occur. No excess risk vs. placebo seen in pooled clinical trial data.

Interactions

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

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

Overdosage

High doses of Spiriva may lead to anticholinergic signs and symptoms.

However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 micrograms tiotropium in healthy volunteers.

Bilateral conjunctivitis in addition to dry mouth was seen in healthy volunteers following repeated once daily inhalation of 141 micrograms tiotropium, which resolved while still under treatment. In a multiple dose study in COPD patients with a maximum daily dose of 36 micrograms Spiriva over four weeks dry mouth was the only observed adverse effect attributable to tiotropium.

Acute intoxication by oral ingestion of tiotropium capsules is unlikely due to low oral bioavailability

Pharmaceutical Precautions

Store below 25°C, in a safe place out of the reach of children. Do not freeze.

Medicine Classification

Prescription Medicine

Package Quantities

Each capsule contains 18 micrograms tiotropium equivalent to 22.5 micrograms tiotropium bromide monohydrate.

Cardboard box containing 30 capsules (3 blister strips)

Cardboard box containing HandiHaler device

Cardboard box containing HandiHaler device and 10 capsules (1 blister strip;)

Cardboard box containing HandiHaler device and 30 capsules (3 blister strips)

Further Information

Spiriva® is a registered trademark.

Excipients

Lactose monohydrate

Hard gelatine capsules

Shelf life

After first opening of the blister, use within 9 days

Instructions for use

The HandiHaler® device is especially designed for SPIRIVA. It must not be used to take any other medication.

You can use your HandiHaler® device for up to one year to take your medication.

dust cap mouthpiece base piercing button centre chamber
Open the dust cap by pulling it upwards. Then open the mouthpiece.
Remove a SPIRIVA capsule from the blister (only immediate before use) and place it in the centre chamber, as illustrated. It does not matter which way the capsule is placed in the chamber.
Close the mouthpiece firmly until you hear a click, leaving the dust cap open.
Hold the HandiHaler® device with the mouthpiece upwards and press the piercing button completely in once, and release. This makes holes in the capsule and allows the medication to be released when you breathe in.
Breathe out completely. Important: Please avoid breathing into the mouthpiece at any time.
Raise the HandiHaler® device to your mouth and close your lips tightly around the mouthpiece. Keep your head in an upright position and breathe in slowly and deeply but at a rate sufficient to hear the capsule vibrate. Breathe until your lungs are full; then hold your breath as long as comfortable and at the same time take the HandiHaler® device out of your mouth. Resume normal breathing. Repeat step 5 and 6 once, this will empty the capsule completely.
Open the mouthpiece again. Tip out the used capsule and dispose. Close the mouthpiece and dust cap for storage of your HandiHaler® device.
Clean the HandiHaler® device once a month. Open the dust cap and mouthpiece. Then open the base by lifting the piercing button. Rinse the complete inhaler with warm water to remove any powder. Dry the HandiHaler® device thoroughly by tipping excess of water out on a paper towel and air-dry afterwards, leaving the dust cap, mouthpiece and base open. It takes 24 hours to air dry, so clean it right after you used it and it will be ready for your next dose. Outside of the mouthpiece may be cleaned with a moist but not wet tissue if needed.

Blister handling Separate the blister strips by tearing along the perforation.
Peel back (only immediately before use) using the tab until one capsule is fully visible.  In case a second capsule is exposed to air inadvertently this capsule has to be discarded.
Remove capsule