Spiriva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SPIRIVAÒ (SPIRIVAÒ)

Composition:

Active substance: tiotropium bromide;

1 capsule contains 22.5 mcg of tiotropium bromide monohydrate, equivalent to 18 mcg of tiotropium;

Excipients: micronized lactose monohydrate, lactose monohydrate 200 M.

Pharmaceutical form. Powder for inhalation, hard capsules.

Main physicochemical properties: hard gelatin capsules size 3 containing white powder, for use with the HANDIHELER device;

capsule shell: according to the corresponding manufacturing procedure, light green, opaque, with a black imprint of the company symbol / TI 01.

Pharmacotherapeutic group. Other agents for treatment of obstructive airway diseases, inhaled agents. Anticholinergic agents.

ATC code R03B B04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Tiotropium bromide is a long-acting specific antagonist of the muscarinic receptor, commonly referred to in clinical practice as an anticholinergic agent. It has similar affinity for all muscarinic receptor subtypes (from M1 to M5). In the airways, complete and reversible inhibition of M3 receptors by tiotropium bromide results in relaxation of smooth muscle. The bronchodilating effect was dose-dependent and lasted more than 24 hours.

The duration of effect is likely due to very slow dissociation from M3 receptors; the half-life of tiotropium is significantly longer than that of ipratropium. As a quaternary nitrogen anticholinergic, tiotropium bromide is locally (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic dose range before systemic anticholinergic effects occur.

Pharmacodynamic effects. Bronchodilation following tiotropium inhalation is primarily a local effect in the airways and is not systemic.

Dissociation from M2 receptors occurs faster than from M3 receptors, which in in vitro functional studies resulted in (kinetically determined) selective action on the M3 receptor subtype compared to M2. High activity and slow dissociation from receptors clinically correlated with significant and prolonged bronchodilation in patients with chronic obstructive pulmonary disease (COPD).

Cardiac electrophysiology

In a dedicated QT interval study involving 53 healthy volunteers, administration of SPIRIVA at doses of 18 mcg and 54 mcg (three times 18 mcg) for 12 days did not cause QT interval prolongation on electrocardiograms.

Clinical efficacy and safety

The clinical trial program included four one-year, two six-month randomized, double-blind studies involving 2663 patients (of whom 1308 received tiotropium bromide). The one-year program consisted of two placebo-controlled studies and two studies with active control (ipratropium). Both six-month studies included comparisons with salmeterol and placebo. All studies evaluated the drug's effect on lung function and outcomes related to dyspnea, exacerbations, and health-related quality of life.

Lung function

Administration of tiotropium bromide once daily resulted in significant improvement in lung function (increased forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)) within 30 minutes after the first dose, with effects lasting 24 hours. Pharmacodynamic steady state was achieved within one week. Bronchodilation occurred by day 3 in most patients.

Daily measurements showed that tiotropium bromide significantly improved morning and evening peak expiratory flow rates.

The bronchodilating effect of tiotropium bromide was maintained throughout the study period (1 year) without evidence of tolerance development.

A randomized, placebo-controlled clinical study involving 105 COPD patients demonstrated that bronchodilation lasted throughout the 24-hour dosing interval compared to placebo, regardless of whether the drug was administered in the morning or evening.

Clinical studies (up to 12 months duration)

Dyspnea, exercise tolerance

Tiotropium bromide significantly reduced dyspnea (assessed using the transitional dyspnea index). Improvement was maintained throughout the treatment period.

The effect of the drug on exercise-induced dyspnea was evaluated in two randomized, double-blind, placebo-controlled studies involving 433 patients with moderate to severe COPD. In these studies, six weeks of treatment with SPIRIVA significantly increased endurance exercise time limited by symptom onset, as measured by cycle ergometry at 75% of maximum capacity, by 19.7% (Study A) and 28.3% (Study B) compared to placebo.

Health-related quality of life

In a randomized, double-blind, placebo-controlled clinical study of 9 months' duration involving 492 patients, the medicinal product SPIRIVA improved the overall health-related quality of life score assessed using the St. George's Respiratory Questionnaire (SGRQ). The number of patients receiving SPIRIVA who achieved a significant improvement in the total SGRQ score (i.e., >4 units) was 10.9% higher than in the placebo group (59.1% in the SPIRIVA group vs. 48.2% in the placebo group (p = 0.029)). The mean difference between groups was 4.19 units (p = 0.001; confidence interval: 1.69–6.68). Improvements in SGRQ subscores were: 8.19 units for "symptoms," 3.91 units for "activity," and 3.61 units for "impact on daily life." Improvements in all these subscores were statistically significant.

COPD exacerbations

In a randomized, double-blind, placebo-controlled study involving 1829 patients with moderate to very severe COPD, tiotropium bromide significantly reduced the proportion of patients experiencing COPD exacerbations (from 32.2% to 27.8%) and significantly reduced the number of exacerbations by 19% (from 1.05 to 0.85 events/patient-year). Hospitalization due to COPD exacerbation occurred in 7.0% of the tiotropium bromide group and 9.5% of the placebo group (p = 0.056). The number of patients hospitalized for COPD was 30% lower (from 0.25 to 0.18 events/patient-year).

In a randomized, double-blind study with two parallel placebo groups lasting 1 year, the effect of treatment with SPIRIVA 18 mcg once daily and salmeterol metered-dose aerosol 50 mcg twice daily on the frequency of moderate and severe exacerbations was evaluated in 7376 COPD patients who had experienced an exacerbation in the previous year.

Compared to salmeterol, SPIRIVA treatment prolonged the time to first exacerbation (187 days vs. 145 days), reducing the risk of exacerbation by 17% (hazard ratio 0.83; 95% confidence interval (CI) 0.77, 0.90, p < 0.001). SPIRIVA inhalation also prolonged the time to first severe exacerbation (hospitalization) (hazard ratio 0.72; 95% CI 0.61, 0.85; p < 0.001).

Long-term clinical studies (more than 1 year, up to 4 years)

In a randomized, double-blind, placebo-controlled clinical study of 4 years' duration involving 5993 randomized patients (3006 receiving placebo and 2987 receiving SPIRIVA), improved FEV1 was demonstrated with SPIRIVA compared to placebo. The proportion of patients completing treatment after ≥45 months was higher in the SPIRIVA group than in the placebo group (63.8% vs. 55.4%, p < 0.001). The annual rate of FEV1 decline was similar in the SPIRIVA and placebo groups. During treatment, a 16% reduction in mortality risk was recorded. The overall number of deaths was 4.79 per 100 patient-years in the placebo group compared to 4.10 per 100 patient-years in the tiotropium group (risk ratio (tiotropium/placebo) = 0.84, 95% CI 0.73, 0.97). Tiotropium treatment reduced the risk of respiratory failure (based on adverse event reporting) by 19% (2.09 vs. 1.68 events per 100 patient-years, relative risk (tiotropium/placebo) 0.81, 95% CI 0.65, 0.999).

Studies with active comparator

A long-term, large-scale, randomized, double-blind study with active control and up to 3 years of follow-up was conducted to compare the efficacy and safety of SPIRIVA with the HANDIHALER device versus SPIRIVA RESPIMAT (5694 patients used SPIRIVA HANDIHALER; 5711 patients used SPIRIVA RESPIMAT). Primary endpoints were time to first COPD exacerbation, time to death from any cause, and, in a substudy (906 patients), trough FEV1 (pre-dose).

Time to first COPD exacerbation during the study was numerically comparable between the SPIRIVA HANDIHALER and SPIRIVA RESPIMAT groups (hazard ratio (SPIRIVA HANDIHALER/SPIRIVA RESPIMAT) 1.02; 95% CI 0.97, 1.08). Mean time to first COPD exacerbation was 719 days for SPIRIVA HANDIHALER and 756 days for SPIRIVA RESPIMAT.

The bronchodilatory effect of SPIRIVA HANDIHALER lasted over 120 weeks and was similar to that of SPIRIVA RESPIMAT. The mean difference in trough FEV1 for SPIRIVA HANDIHALER compared to SPIRIVA RESPIMAT was 0.010 liters (95% CI –0.018, 0.038 liters).

In the post-marketing comparative TIOSPIR study of SPIRIVA RESPIMAT and SPIRIVA with HANDIHALER device, similar all-cause mortality rates, including vital status monitoring, were demonstrated in the studied drug groups (hazard ratio (SPIRIVA HANDIHALER/SPIRIVA RESPIMAT) 1.04; 95% CI 0.91, 1.19).

Pharmacokinetics. Tiotropium bromide is a non-chiral quaternary ammonium compound with moderate water solubility. Tiotropium is administered as a dry powder for inhalation. Typically, after inhalation, the majority of the released dose deposits in the gastrointestinal tract, with a smaller amount reaching the lungs. Many of the pharmacokinetic data described below were obtained using doses higher than those recommended for treatment.

Absorption. After inhalation of the dry powder, absolute bioavailability is 19.5%, indicating high bioavailability of the fraction reaching the lungs. Absolute bioavailability of the oral solution of tiotropium is 2–3%. Maximum plasma concentration of tiotropium was observed 5–7 minutes after inhalation.

At steady state, maximum plasma concentration of tiotropium in COPD patients was 12.9 pg/mL and rapidly declined according to a multicompartment model. Trough plasma concentration of tiotropium at steady state was 1.71 pg/mL. Systemic exposure after inhalation of tiotropium via the HANDIHALER device was similar to that after inhalation via the RESPIMAT inhaler.

Distribution. 72% of the drug is plasma protein-bound. Volume of distribution is 32 L/kg. Local concentration in the lungs is unknown, but based on the route of administration, high lung concentration is expected. Studies in rats have shown that tiotropium does not significantly penetrate the blood-brain barrier.

Biotransformation. The extent of biotransformation is low, as 74% of the unchanged substance was excreted in urine after intravenous administration to young healthy volunteers. As an ester, tiotropium undergoes non-enzymatic degradation to N-methylscopolamine and dithienylglycolic acid, neither of which binds to muscarinic receptors.

Further in vitro studies on human liver microsomes and hepatocytes show that tiotropium (<20% of the dose after intravenous administration) is metabolized via cytochrome P450-dependent oxidation and subsequent glutathione conjugation to various phase II metabolites. In vitro studies on human liver microsomes indicate that this enzymatic pathway may be inhibited by CYP450 2D6 (and 3A4) inhibitors such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in metabolic transformations responsible for elimination of a minor fraction of the dose. Tiotropium, even at supratherapeutic concentrations, does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A in human liver microsomes.

Elimination. The effective half-life of tiotropium ranges between 27 and 45 hours after administration in COPD patients. Total clearance was 880 mL/min after intravenous administration to young healthy volunteers. After intravenous administration, tiotropium is primarily excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion of unchanged drug is 7% (1.3 mcg) of the administered dose over 24 hours; the remainder is unabsorbed by the intestine and excreted in feces. Renal clearance of tiotropium exceeds creatinine clearance, indicating active renal excretion. After continuous daily inhalation in COPD patients, pharmacokinetic steady state is reached within 7 days without further accumulation.

Linearity/non-linearity. Tiotropium exhibits linear pharmacokinetic properties within the therapeutic range, regardless of dosage form.

Pharmacokinetics in elderly patients. As with all other drugs primarily excreted in urine, renal clearance of tiotropium is reduced in elderly patients (365 mL/min in COPD patients <65 years vs. 271 mL/min in COPD patients ≥65 years). This did not lead to a corresponding increase in AUC0–6,ss or Cmax,ss values.

Pharmacokinetics in patients with renal impairment. Once-daily inhalation of tiotropium in COPD patients at steady state with mild renal impairment (creatinine clearance 50–80 mL/min) resulted in a slight increase in AUC0–6,ss (1.8–30%) and similar Cmax values compared to patients with normal renal function (creatinine clearance >80 mL/min).

In COPD patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), intravenous administration of tiotropium leads to a doubling of total exposure (AUC0–4h 82% higher, Cmax 52% higher) compared to patients with normal renal function, confirmed by plasma concentration data after dry powder inhalation.

Pharmacokinetics in patients with hepatic impairment. Hepatic impairment has no significant effect on the pharmacokinetics of tiotropium. Tiotropium is primarily eliminated via renal excretion (up to 74% in young healthy volunteers) and by simple non-enzymatic ester cleavage into products that do not bind to muscarinic receptors.

Patients with COPD of Japanese origin. In cross-over comparisons, mean maximum plasma concentration of tiotropium 10 minutes after dosing at steady state was 20–70% higher in Japanese compared to European patients after tiotropium inhalation, but there were no signs of increased mortality or cardiac risk in Japanese patients compared to Europeans. There are insufficient pharmacokinetic data for other races or ethnic groups.

Pharmacokinetic/pharmacodynamic relationship. There is no direct relationship between pharmacokinetics and pharmacodynamics.

Clinical characteristics.

Indications.

Maintenance bronchodilator therapy for symptomatic relief in chronic obstructive pulmonary disease (COPD).

Contraindications.

Spiriva inhalation powder is contraindicated in patients with known hypersensitivity to tiotropium bromide, atropine or its derivatives (such as ipratropium or oxitropium), or to any of the excipients of the product.

Interaction with other medicinal products and other forms of interaction.

Although formal studies of interactions with other medicinal products have not been conducted, tiotropium bromide has been used concomitantly with other medications (sympathomimetic bronchodilators, methylxanthines, oral and inhaled corticosteroids used in the treatment of COPD) without clinical evidence of interactions with other medicinal products.

It has not been shown that the use of long-acting beta-adrenoceptor agonists or inhaled corticosteroids alters tiotropium exposure.

However, the co-administration of Spiriva with other anticholinergic medicinal products has not been studied and therefore is not recommended.

Special precautions for use

Tiotropium bromide is a bronchodilator administered once daily for maintenance therapy and is not intended for the initial treatment of acute bronchospasm attacks or for relief of acute symptoms.

Immediate-type hypersensitivity reactions may occur after administration of SPIRIVA.

Like other anticholinergic agents, SPIRIVA should be used with caution in patients with closed-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction (see section "Adverse reactions").

Inhaled medications may induce inhalation-related bronchospasm.

SPIRIVA should be used with caution in patients who have recently experienced myocardial infarction (within <6 months); in patients with any unstable or life-threatening arrhythmia, or arrhythmia requiring intervention or change in therapy within the past year; and in patients who have been hospitalized due to heart failure (NYHA class III or IV) within the past year. These patient groups were excluded from clinical trials. Anticholinergic effects may be harmful in such conditions.

Since plasma concentrations of tiotropium bromide increase in patients with moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min), SPIRIVA should be administered only if the expected benefit outweighs the potential risk. Data on long-term use of SPIRIVA in patients with renal impairment are lacking (see section "Pharmacokinetics").

Patients should avoid getting the powder into their eyes. They should be warned that this may lead to precipitation or worsening of closed-angle glaucoma, eye pain or discomfort, temporary blurred vision, perception of halos or colored images, in combination with eye redness due to conjunctival or corneal hyperemia.

If any of the above symptoms occur in any combination, patients should discontinue use of tiotropium bromide and seek immediate specialized medical assistance.

Dry mouth, commonly observed during anticholinergic therapy, may potentially contribute to dental caries over time.

SPIRIVA should not be used more than once daily.

SPIRIVA contains 5.5 mg of lactose monohydrate per capsule. This amount generally does not cause problems in patients with lactose intolerance. However, the use of this medication is not recommended in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption. The excipient lactose monohydrate may contain trace amounts of milk proteins that could trigger allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of tiotropium in pregnant women are very limited. Preclinical studies have not revealed any direct or indirect harmful effects related to reproductive toxicity at clinically relevant doses. As a precautionary measure, use of SPIRIVA during pregnancy should be avoided.

Breastfeeding. It is unknown whether tiotropium bromide is excreted in human breast milk. Although animal studies have shown only minimal excretion of tiotropium bromide into breast milk, use of the drug during breastfeeding is not recommended.

Tiotropium bromide is a long-acting compound. The decision whether to continue or discontinue breastfeeding or to continue or discontinue SPIRIVA therapy should be made after considering the benefits of breastfeeding for the infant and the benefits of therapy for the mother.

Fertility. There are no available clinical data on the effect of tiotropium on fertility. Preclinical studies of tiotropium have not shown any adverse effects on fertility.

Ability to affect reaction speed when driving or operating machinery

No studies on the effect on the ability to drive cars or operate machinery have been conducted. The occurrence of dizziness, headache, or blurred vision may affect the ability to drive or operate machinery.

Method of Administration and Dosage

Dosing

The medicinal product is intended for inhalation use only.

The recommended dose of tiotropium bromide is inhalation of the contents of one capsule once daily using the HandiHaler inhalation device. Inhalation should be performed at the same time each day.

The recommended dose should not be exceeded.

SPIRIVA capsules are not intended for oral administration.

SPIRIVA capsules must not be swallowed.

SPIRIVA capsules should be used only with the HandiHaler inhalation device.

Special Populations

Elderly patients may use tiotropium bromide according to the dose recommended by the physician.

Patients with renal impairment may use tiotropium bromide according to the dose recommended by the physician. Information on the use of SPIRIVA in patients with moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) is provided in the sections "Special Instructions" and "Pharmacokinetics".

Patients with hepatic impairment may use SPIRIVA according to the dose recommended by the physician (see section "Pharmacokinetics").

Mucoviscidosis (Cystic Fibrosis). Safety and efficacy of SPIRIVA 18 mcg in children and adolescents have not been established. Data are lacking.

Instructions for Use

The HandiHaler is an inhalation device specifically designed to allow patients to inhale medication contained in SPIRIVA capsules. The HandiHaler device must not be used for any other medications. It is a single-patient device intended for repeated use.

To ensure proper use of the medication, patients must be instructed on how to use the inhaler.

To use the HandiHaler inhalation device, patients should follow the steps outlined below.

When using SPIRIVA, patients should follow their physician's recommendations.

After first use, the HandiHaler inhalation device may be used for one year, provided it is used as directed.

SPIRIVA capsules contain only a small amount of powder, so the capsule is only partially filled.

Children.

The medication is not intended for use in children (under 18 years of age).

Overdose.

High doses of SPIRIVA may cause anticholinergic signs and symptoms.

However, systemic anticholinergic adverse effects were absent in healthy volunteers after single doses up to 340 mcg of tiotropium bromide.

No significant adverse reactions other than dry mouth were observed after 7 days of administration of tiotropium bromide up to 170 mcg in healthy volunteers.

In multiple-dose studies in patients with COPD, administration of the maximum daily dose of 43 mcg of tiotropium bromide for 4 weeks did not result in significant adverse reactions.

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

Adverse Reactions

Summary of safety information on the use of the medicinal product

Many of the listed adverse effects can be attributed to the anticholinergic properties of SPIRIVA.

Adverse reactions to the drug were identified based on data from clinical trials and spontaneous reports during the post-marketing period. The clinical study database includes 9,647 patients who received tiotropium in 28 placebo-controlled clinical trials with treatment duration ranging from 4 weeks to 4 years.

Frequency of adverse reactions according to MedDRA:

Very common (≥ 1/10);
Common (≥ 1/100, < 1/10);
Uncommon (≥ 1/1,000, < 1/100);
Rare (≥ 1/10,000, < 1/1,000);
Very rare (< 1/10,000);
Not known (cannot be estimated from available data).

Metabolism and nutrition disorders:

Not known – dehydration.

Nervous system disorders:

Uncommon – dizziness, headache, taste disturbance;
Rare – insomnia.

Eye disorders:

Uncommon – blurred vision;
Rare – glaucoma, increased intraocular pressure.

Cardiac disorders:

Uncommon – atrial fibrillation;
Rare – supraventricular tachycardia, tachycardia, palpitations.

Respiratory, thoracic and mediastinal disorders:

Uncommon – pharyngitis, dysphonia, cough;
Rare – bronchospasm, epistaxis, laryngitis, sinusitis.

Gastrointestinal disorders:

Common – dry mouth;
Uncommon – gastroesophageal reflux disease, constipation, oral candidiasis;
Rare – intestinal obstruction, including paralytic ileus; glossitis, dysphagia, stomatitis, nausea;
Not known – dental caries.

Skin and subcutaneous tissue disorders and immune system disorders:

Uncommon – rash;
Rare – urticaria, pruritus, hypersensitivity (including immediate-type allergic reactions), angioedema;
Not known – anaphylactic reaction, skin infections and ulceration, dry skin.

Musculoskeletal and connective tissue disorders:

Not known – joint swelling.

Renal and urinary disorders:

Uncommon – dysuria, urinary retention;
Rare – urinary tract infection.

Description of selected adverse reactions

In controlled clinical studies, the anticholinergic adverse reaction dry mouth was commonly observed, occurring in approximately 4% of patients.

In 28 clinical trials, dry mouth led to discontinuation of the drug in 18 out of 9,647 patients (0.2%).

Among serious adverse effects consistent with anticholinergic effects are glaucoma, constipation, intestinal obstruction (including paralytic ileus), and urinary retention.

Other special patient groups

The number of anticholinergic effects may increase with age.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After first opening of the blister strip, use within 9 days.

Storage conditions. Store at a temperature not exceeding 25 °C. Protect from direct sunlight, heat, and frost. Keep out of reach of children.

Packaging. 10 capsules with powder for inhalation in a blister; 3 blisters per cardboard box.

10 capsules with powder for inhalation in a blister; 1 or 3 blisters supplied with the HANDIHELER device in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.

Manufacturer's address and place of business.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.