Tiodora

TIODORA 18

Composition

Each Capsule Contains:

Tiotropium as Tiotropium

bromide monohydrate ……18 mcg

Excipients ….q.s.

Approved colours used in empty capsule.

Chemical Name

(1a, 2ß, 4ß, 5a, 7ß-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9 azoniatricyclo[3.3.1.02,4]nonane bromide monohydrate, Tiotropium bromide monohydrate

Category

Tiotropium is a long-acting, antimuscarinic agent.

DESCRIPTION

White to off white powder  filled in Size ” 3 ”  Stick free Capsules with Green colour Cap/ Clear transparent coloured body capsule, imprinted ‘3TM 018’ on Cap in Blue Ink.

CLINICAL PHARMACOLOGY

Mechanism of Action

Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic.  In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation.

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.

Absorption

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.

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.

Elimination

The terminal elimination half-life of tiotropium is between 5 and 6 days following inhalation.

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.

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.

Plasma concentrations were numerically increased with advancing age within COPD patients which was not significant when considered in relation to inter- and intra-individual variability

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

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.

INDICATIONS AND USAGE

Tiotropium bromide inhalation powder is indicated for the long-term,once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

CONTRAINDICATIONS

Tiotropium bromide inhalation powder is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, including ipratropium, or to any component of this product.

WARNINGS

Tiotropium bromide inhalation  powder is intended as a once-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm, i.e., rescue therapy.

Immediate hypersensitivity reactions, including angioedema, may occur after administration of tiotropium. If such a reaction occurs, therapy with tiotropium should be stopped at once and alternative treatments should be considered.

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

Tiotropium capsules are for inhalation only and must not be swallowed.

PRECAUTIONS

As an anticholinergic drug, tiotropium bromide inhalation powder may potentially worsen symptoms and signs associated with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction and should be used with caution in patients with any of these conditions.

As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of £ 50 mL/min) treated with tiotropium should be monitored .

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Tiotropium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in Labor and Delivery

The safety and effectiveness of tiotropium has not been studied during labor and delivery.

Nursing Mothers

Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if tiotropium is administered to a nursing woman.

Pediatric Use

Tiotropium inhaler is approved for use in the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. This disease does not normally occur in children. The safety and effectiveness of tiotropium in pediatric patients have not been established.

ADVERSE REACTIONS

The most commonly adverse drug reaction is dry mouth. It is often mild and resolved during continued treatment. Other reactions which are not common includes constipation, increased heart rate, blurred vision, glaucoma, urinary difficulty, and urinary retention.

DOSAGE AND ADMINISTRATION

The recommended dosage of Tiotropium bromide inhalation powder is the inhalation of the contents of one tiotropium capsule, once-daily, with the inhalation device. No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given tiotropium should be monitored closely.

Presentation

30 Capsules in a bottle.

Shelf life

18 Months

Storage

Store in a cool & dry place below 30°C.