Composition

TIOVA Rotacaps

Each rotacap contains:

Tiotropium (as Tiotropium Bromide Monohydrate) …… 18 mcg

Excipient……………..q.s.

Dosage Form

Dry powder for inhalation

Pharmacology

Pharmacodynamics

Tiotropium is a long-acting, anti-muscarinic 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 pre-clinical in vitro as well as in vivo studies, prevention of methacholine induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The long duration is probably due to the very slow dissociation from the M₃ receptor, exhibiting a significantly longer dissociation half-life than ipratropium. As an N-quaternary anticholinergic, tiotropium bromide when administered by inhalation, demonstrates acceptable therapeutic range before systemic anticholinergic effects may occur. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect. 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.

Electrophysiology:

In a dedicated QT study involving 53 healthy volunteers, tiotropium 18 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not significantly prolong QT intervals of the ECG.

Pharmacokinetics

Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. 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 lungs, 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 lungs 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 (10-15%). 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 5–7 minutes after inhalation. At steady state, peak tiotropium plasma levels in COPD patients were 12.9 pg/mL and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.71 pg/mL.

Distribution

Tiotropium shows a volume of distribution of 32 L/kg. The drug is bound by 72% to plasma proteins. Local concentrations in the lungs are not known, but the mode of administration suggests substantially higher concentrations in the lungs. 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 non-enzymatically cleaved to the alcohol (N-methylscopine) and dithienylglycolic acid, neither of which binds to muscarinic receptors.

In vitro experiments with human liver microsomes and human hepatocytes suggest that that some further drug (< 20% of dose after intravenous administration) is metabolized by cytochrome P-450dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites.

In vitro studies using human liver microsomes found that this enzymatic pathway can be inhibited by CYP2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP2D6 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 CYP1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

Elimination

The effective half-life of tiotropium ranges between 27-45 hours in COPD patients. After an intravenous dose in young healthy volunteers, total clearance was 880 mL/min. Intravenously administered tiotropium is mainly excreted unchanged in the urine (74%). After dry powder inhalation by COPD patients to steady-state, urinary excretion is 7% (1.3 mcg) of the unchanged drug over 24 hours, the remainder being mainly non-absorbed drug in the gut, which is eliminated via the faeces. The renal clearance of tiotropium exceeds the creatinine clearance (CrCl), indicating active secretion into the urine. After continual once-daily inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.

Special Populations

Elderly Patients

As expected for drugs predominantly excreted renally, advanced age was associated with a decrease of tiotropium renal clearance (365 mL/min in COPD patients < 65 years to 271 mL/min in COPD patients ≥ 65 years), which may be explained by decreased renal function. This did not result in a corresponding increase in AUC_0-6,ss or C_max,_ss values.

Hepatically-impaired Patients

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

Renally-impaired Patients

Following once daily inhaled administrations of tiotropium to steady-state in COPD patients, mild renal impairment (CL_CR 50-80 ml/min) resulted in slightly higher AUC_0-6,ss (between 1.8-30% higher) and similar C_{max, ss} values compared to patients with normal renal function(CL_CR >80 ml/min).

Mild renal impairment (CrCl of 50–80 mL/min), which is often seen in elderly patients, increased tiotropium plasma concentrations (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 total exposure (82% increase in AUC_0–4h and 52% higher C_max), compared to COPD patients with normal renal function, which was confirmed by plasma concentrations after dry powder inhalation.

Indication

TIOVA Rotacaps are indicated for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema.

Dosage and Aministration

The recommended dosage of TIOVA Rotacaps is one rotacap inhaled once daily, using the Cipla Rotahaler/ Revolizer.

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment, who are being treated with TIOVA Rotacaps, should be monitored closely.

TIOVA Rotacaps are for inhalation only and must not be swallowed.

Contraindications

TIOVA Rotacaps are contraindicated in patients with a history of hypersensitivity to tiotropium, atropine or its derivatives, including ipratropium, or to any component of this product.

Warnings and Precautions

TIOVA Rotacaps are intended as a once-daily maintenance treatment for COPD and are not indicated for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy. In the event of an acute attack, a rapid-acting beta₂-agonist should be used.

If such a reaction occurs, therapy with TIOVA Rotacaps should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to TIOVA Rotacaps. In addition, TIOVA Rotacaps should be used with caution in patients with severe hypersensitivity to milk proteins.

Inhaled medicines, including TIOVA Rotacaps, may cause paradoxical bronchospasm. If this occurs, treatment with TIOVA Rotacaps should be stopped and other treatments considered.

Tiotropium should be used with caution in patients with known cardiac rhythm disorders. Tiotropium should be used with caution in patients with recent myocardial infarction < 6 months; any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation of heart failure (NYHA Class III or IV) within the past year. These patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action.

TIOVA Rotacaps should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. Also in general, patients should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in the precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema. In such a case, patients should stop using TIOVA Rotacaps and consult a specialist immediately.

Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Patients should consult a physician immediately should any of these signs or symptoms develop.

As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) TIOVA Rotacaps should be used only if the expected benefit outweighs the potential risk. There is no long term experience in patients with severe renal impairment. Dry mouth, which has been observed with anti-cholinergic treatment, may in the long term be associated with dental caries.

Tiotropium bromide should not be used more frequently than once daily.

Drug Interactions

Although no formal drug interaction studies have been performed, tiotropium bromide has been used concomitantly with other drugs commonly used in COPD and asthma without clinical evidences of drug interactions. These include sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leukotriene modifiers, cromones, anti-IgE treatment. Use of LABA or ICS was not found to alter the exposure to tiotropium.

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

Renal impairment

Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with TIOVA Rotacaps should be monitored closely for anticholinergic side effects.

Hepatic impairment

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses.

As a precautionary measure, it is preferable to avoid the use of TIOVA Rotacaps during pregnancy.

Lactation

Clinical data from nursing mothers exposed to tiotropium are not available. Based on studies in lactating rodents, tiotropium is excreted into breast milk only in small amounts. It is not known whether tiotropium is excreted into human milk, but because many drugs are excreted into human milk and given the findings in rats, caution should be exercised if tiotropium bromide is administered to a nursing mother.

Paediatric Use

TIOVA Rotacaps are approved for use in the maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema. This disease does not normally occur in children. The safety and effectiveness of tiotropium bromide in paediatric patients have not been established. The efficacy and safety of Tiotropium in children and adolescents has not yet been established.

Geriatric Use

Instances of dry mouth increased with age in patients receiving tiotropium bromide. A higher frequency of constipation and urinary tract infections with increasing age was observed in the tiotropium bromide group in the placebo-controlled studies. No overall differences in effectiveness were observed among various age groups. Based on available data, no adjustment of tiotropium bromide dosage in geriatric patients is warranted.

Undesirable Effects

Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium. In COPD, the frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (9,647 patients) from 28 pooled placebo-controlled clinical trials in COPD with treatment periods ranging from four weeks to four years.

In patients with COPD, the common (≥1/100 to <1/10) adverse reaction includes dry mouth; the uncommon (≥1/1,000 to <1/100) adverse reactions include dizziness, headache, taste disorders, blurred vision, atrial fibrillation, cough, pharyngitis, dysphonia, constipation, gastroesophageal reflux disease, oropharyngeal candidiasis, rash, dysuria and urinary retention; rare (≥1/10,000 to <1/1,000) adverse reactions include insomnia, glaucoma, increased intraocular pressure, supraventricular tachycardia, tachycardia, palpitations, bronchospasm, epistaxis, laryngitis, sinusitis, intestinal obstruction, including ileus paralytic, gingivitis, glossitis, dysphagia, stomatitis, nausea, urticaria, pruritus, hypersensitivity (including immediate reactions), angioedema and urinary tract infection; not known (cannot be estimated from the available data) adverse reactions include: dehydration, dental caries, anaphylactic reaction, skin infection, skin ulcer, dry skin, joint swelling.

In controlled clinical studies, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 4% of patients.

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

Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation and intestinal obstruction including ileus paralytic as well as urinary retention.

An increase in anticholinergic effects may occur with increasing age.

Overdosage

High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 340 mcg of tiotropium in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth, were observed following a 7-day dosing of up to 170 mcg of tiotropium bromide in healthy volunteers. In a multiple-dose study in COPD patients with a maximum daily dose of 43 mcg of tiotropium bromide over 4 weeks, no significant undesirable effect has been observed.

Acute intoxication by inadvertent oral ingestion of tiotropium bromide rotacaps is unlikely, since it is not well absorbed systemically.

Packinging Information

TIOVA Rotacaps........... Each sales pack contains 15 Rotacaps

Last updated: May 2016
Last reviewed: May 2016